Hairy cell leukemia
Encyclopedia
Hairy cell leukemia is an uncommon hematological malignancy
characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia. Hairy cell leukemia makes up approximately 2% of all leukemia
s, with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.
Hairy cell leukemia was originally described as histiocytic leukemia, malignant reticulosis, or lymphoid myelofibrosis in publications dating back to the 1920s. The disease was formally named leukemic reticuloendotheliosis and its characterization significantly advanced by Bertha Bouroncle and colleagues at The Ohio State University College of Medicine
in 1958. Its common name, which was coined in 1966, is derived from the "hairy" appearance of the malignant B cells under a microscope.
Similar to B-PLL in Chronic Lymphocytic Leukemia
, HCL-V is a more aggressive disease. It is less likely to be treated successfully than classic HCL and remissions tend to be shorter. Many treatment approaches, such as Interferon
-alpha, CHOP and common alkylating agents like cyclophosphamide
provide very little benefit. Pentostatin and cladribine provide some benefit to many HCL-V patients, but with shorter remissions and lower response rates compared to classic HCL. More than half of patients respond partially to splenectomy.
In terms of B cell development, the prolymphocytes are less developed than lymphocyte
cells or plasma cells, but are still more developed than their lymphoblastic precursors.
HCL-V differs from classic HCL principally in these respects:
The lack of CD25, which is part of the receptor for a key immunoregulating hormone, may explain why HCL-V cases are normally resistant to treatment by immune system hormones.
HCL-V, which has a high proportion of hairy cells without a functional p53
tumor suppressor gene, is somewhat more likely to transform into a higher-grade disease, with Daniel Catovsky suggesting a typical transformation rate of 5% in the U.K., which is similar to the Richter's transformation
rate for SLVL and CLL and reporting 6% in one group of patients. Among HCL-V patients, the most aggressive cases normally have the least amount of p53 gene activity. Hairy cells without the p53 gene tend, over time, to displace the less aggressive p53+ hairy cells.
Treatment with cladribine
has been reported.
, anemia
and fatigue due to a lack of red blood cells, or easy bleeding due to a low platelet count
. Leukemic cells may gather in the spleen
and cause it to swell; this can have the side effect of making the person feel full even when he or she has not eaten much.
Hairy cell leukemia is commonly diagnosed after a routine blood count shows unexpectedly low numbers of one or more kinds of normal blood cells, or after unexplained bruises or recurrent infections in an otherwise apparently healthy patient.
Platelet function may be somewhat impaired in HCL patients, although this does not appear to have any significant practical effect. It may result in somewhat more mild bruises than would otherwise be expected for a given platelet count or a mildly increased bleeding time for a minor cut. It is likely the result of producing slightly abnormal platelets in the overstressed bone marrow tissue.
Patients with a high tumor burden may also have somewhat reduced levels of cholesterol, especially in patients with an enlarged spleen. Cholesterol levels return to more normal values with successful treatment of HCL.
, or industrial chemicals (with the possible exception of diesel) does not appear to increase the risk of developing HCL. Farming and gardening appear to increase the risk of HCL in some studies.
Recent studies have identified somatic BRAF V600E mutations in all patients with the classic form of hairy cell leukemia thus sequenced, but in no patients with the variant form..
The U.S. Institute of Medicine
(IOM) announced "sufficient evidence" of an association between exposure to herbicides and later development of chronic B-cell leukemias and lymphomas in general. The IOM report emphasized that neither animal nor human studies indicate an association of herbicides with HCL specifically. However, the IOM extrapolated data from chronic lymphocytic leukemia and non-Hodgkin lymphoma
to conclude that HCL and other rare B-cell neoplasms may share this risk factor. As a result of the IOM report, the U.S. Department of Veterans Affairs
considers HCL an illnesses presumed to be a service-related disability (see Agent Orange
).
Human T-lymphotropic virus 2
(HTLV-2) has been isolated in a small number of patients with the variant form of HCL. In the 1980s, HTLV-2 was identified in a patient with a T-cell lymphoproliferative disease; this patient later developed hairy cell leukemia (a B cell disease), but HTLV-2 was not found in the hairy cell clones. There is no evidence that HTLV-II causes any sort of hematological malignancy, including HCL.
(CBC), but additional testing is necessary to confirm the diagnosis. A CBC normally shows low counts for white blood cells, red blood cells, and platelets in HCL patients. However, if large numbers of hairy cells are in the blood stream, then normal or even high lymphocyte counts
may be found.
On physical exam, 80–90% of patients have an enlarged spleen
, which can be massive. This is less likely among patients who are diagnosed at an early stage. Peripheral lymphadenopathy
(enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on computed tomography
(CT) scans.
The most important lab finding is the presence of hairy cells in the bloodstream. Hairy cells are abnormal white blood cell
s with hair-like projections of cytoplasm
; they can be seen by examining a blood smear or bone marrow biopsy
specimen. The blood film examination is done by staining the blood cells with Wright's stain and looking at them under a microscope
. Hairy cells are visible in this test in about 85% of cases.
Most patients require a bone marrow biopsy for final diagnosis. The bone marrow biopsy is used both to confirm the presence of HCL and also the absence of any additional diseases, such as Splenic marginal zone lymphoma
or B-cell prolymphocytic leukemia
. The diagnosis can be confirmed by viewing the cells with a special stain known as TRAP (tartrate resistant acid phosphatase
).
It is also possible to definitively diagnose hairy cell leukemia through flow cytometry
on blood or bone marrow. The hairy cells are larger than normal and positive for CD19
, CD20
, CD22
, CD11c
, CD25
, CD103, and FMC7. (CD103, CD22
, and CD11c
are strongly expressed.)
Hairy cell leukemia-variant (HCL-V), which shares some characteristics with B cell prolymphocytic leukemia (B-PLL), does not show CD25 (also called the Interleukin-2 receptor, alpha). As this is relatively new and expensive technology, its adoption by physicians is not uniform, despite the advantages of comfort, simplicity, and safety for the patient when compared to a bone marrow biopsy. The presence of additional lymphoproliferative diseases is easily checked during a flow cytometry test, where they characteristically show different results.
The differential diagnoses include: several kinds of anemia
, including myelophthisis
and aplastic anemia
, and most kinds of blood neoplasms, including hypoplastic myelodysplastic syndrome
, atypical chronic lymphocytic leukemia, B-cell prolymphocytic leukemia
, or idiopathic myelofibrosis
.Table 4. Phenotypic differential diagnosis of hairy cell leukemia]}}
in HCL is caused primarily by marrow failure and splenomegaly
. Bone marrow failure is caused by the accumulation of hairy cells and reticulin fibrosis
in the bone marrow, as well as by the detrimental effects of dysregulated cytokine production. Splenomegaly reduces blood counts through sequestration, marginalization, and destruction of healthy blood cells inside the spleen.
Hairy cells are nearly mature B cell
s, which are activated clonal cells with signs of VH gene differentiation. They may be related to pre-plasma marginal zone
B cells or memory cells.
Cytokine
production is disturbed in HCL. Hairy cells produce and thrive on 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 an immune system protein called Interleukin-2 receptor (IL-2R). In HCL-V, only part of this receptor is expressed. As a result, disease status can be monitored by measuring changes in the amount of IL-2R in the blood serum. The level increases as hairy cells proliferate, and decreases when they are killed. Although uncommonly used in North America and northern Europe, this test correlates better with disease status and predicts relapse more accurately than any other test.
Hairy cells respond to normal production of some cytokines by T cell
s with increased growth. Treatment with Interferon-alpha suppresses the production of this pro-growth cytokine from T cells. A low level of T cells, which is commonly seen after treatment with cladribine
or pentostatin
, and the consequent reduction of these cytokines, is also associated with reduced levels of hairy cells.
In June 2011, E Tiacci et al
discovered that 100% of hairy-cell leukaemia samples analysed had the oncogenic BRAF
mutation V600E, and proposed that this is the disease's driver mutation. Until this point, only a few genomic
imbalances had been found in the hairy cells, such as trisomy
5 had been found. The expression of genes
is also dysregulated in a complex and specific pattern. The cells underexpress 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 yet been demonstrated that any of these changes have any practical significance to the patient.
Not everyone needs treatment. Treatment is usually given when the symptoms of the disease interfere with the patient's everyday life, or when white blood cell or platelet counts decline to dangerously low levels, such as an absolute neutrophil count
below one thousand cells per microliter (1.0 K/uL). Not all patients need treatment immediately upon diagnosis, and about 10% of patients will never need treatment.
Treatment delays are less important than in solid tumors. Unlike most cancers, treatment success does not depend on treating the disease at an early stage. Because delays do not affect treatment success, there are no standards for how quickly a patient should receive treatment. However, waiting too long can cause its own problems, such as an infection that might have been avoided by proper treatment to restore immune system function. Also, having a higher number of hairy cells at the time of treatment can make certain side effects somewhat worse, as some side effects are primarily caused by the body's natural response to the dying hairy cells. This can result in the hospitalization of a patient whose treatment would otherwise be carried out entirely at the hematologist's office.
Single-drug treatment is typical. Unlike most cancers, only one drug is normally given to a patient at a time. While monotherapy is normal, combination therapy—typically using one first-line therapy and one second-line therapy—is being studied in current clinical trials and is used more frequently for refractory cases. Combining rituximab with cladribine or pentostatin may or may not produce any practical benefit to the patient. Combination therapy is almost never used with a new patient. Because the success rates with purine analog monotherapy are already so high, the additional benefit from immediate treatment with a second drug in a treatment-naïve patient is assumed to be very low. For example, one round of either cladribine or pentostatin gives the median first-time patient a decade-long remission; the addition of rituximab, which gives the median patient only three or four years, might provide no additional value for this easily treated patient. In a more difficult case, however, the benefit from the first drug may be substantially reduced and therefore a combination may provide some benefit.
(2CDA) and pentostatin
(DCF) are the two most common first-line therapies. They both belong to a class of medications called purine analogs, which have mild side effects compared to traditional chemotherapy
regimens.
Cladribine can be administered by injection under the skin, by infusion over a couple of hours into a vein, or by a pump worn by the patient that provides a slow drip into a vein, 24 hours a day for 7 days. Most patients receive cladribine by IV infusion once a day for five to seven days, but more patients are being given the option of taking this drug once a week for six weeks. The different dosing schedules used with cladribine are approximately equally effective and equally safe.
Relatively few patients have significant side effects other than fatigue and a high fever caused by the cancer cells dying, although complications like infection and acute kidney failure have been seen.
Pentostatin is chemically similar to cladribine, and has a similar success rate and side effect profile, but it is always given over a much longer period of time, usually one dose by IV infusion every two weeks for three to six months.
During the weeks following treatment the patient's immune system
is severely weakened, but their bone marrow
will begin to produce normal blood cells again. Treatment often results in long-term remission. About 85% of patients achieve a complete response from treatment with either cladribine or pentostatin, and another 10% receive some benefit from these drugs, although there is no permanent cure for this disease. If the cancer cells return, the treatment may be repeated and should again result in remission, although the odds of success decline with repeated treatment. Remission lengths vary significantly, from one year to more than twenty years. The median patient can expect a treatment-free interval of about ten years.
It does not seem to matter which drug a patient receives. A patient who is not successfully treated with one of these two drugs has a reduced chance of being successfully treated with the other. However, there are other options.
Monoclonal antibodies The most common treatment for cladribine-resistant disease is infusing monoclonal antibodies that destroy cancerous B cells. Rituximab
is by far the most commonly used. Most patients receive one IV infusion over several hours each week for four to eight weeks. A 2003 publication found two partial and ten complete responses out of 15 patients with relapsed disease, for a total of 80% responding. The median patient (including non-responders) did not require further treatment for more than three years. This eight-dose study had a higher response rate than a four-dose study at Scripps, which achieved only 25% response rate. Rituximab has successfully induced a complete response in Hairy Cell-Variant.
Rituximab's major side effect is serum sickness, commonly described as an "allergic reaction", which can be severe, especially on the first infusion. Serum sickness is primarily caused by the antibodies clumping during infusion and triggering the complement
cascade. Although most patients find that side effects are adequately controlled by anti-allergy drugs, some severe, and even fatal, reactions have occurred. Consequently, the first dose is always given in a hospital setting, although subsequent infusions may be given in a physician's office. Remissions are usually shorter than with the preferred first-line drugs, but hematologic remissions of several years' duration are not uncommon.
Other B cell-destroying monoclonal antibodies such as Alemtuzumab
, Ibritumomab tiuxetan
and I-131 Tositumomab
may be considered for refractory cases.
Interferon-alpha Interferon-alpha is an immune system hormone that is very helpful to a relatively small number of patients, and somewhat helpful to most patients. In about 65% of patients, the drug helps stabilize the disease or produce a slow, minor improvement for a partial response.
The typical dosing schedule injects at least 3 million units of Interferon-alpha (not pegylated versions) three times a week, although the original protocol began with six months of daily injections.
Some patients tolerate IFN-alpha very well after the first couple of weeks, while others find that its characteristic flu-like symptoms persist. About 10% of patients develop a level of depression
. It is possible that, by maintaining a steadier level of the hormone in the body, that daily injections might cause fewer side effects in selected patients. Drinking at least two liters of water each day, while avoiding caffeine and alcohol, can reduce many of the side effects.
A drop in blood counts is usually seen during the first one to two months of treatment. Most patients find that their blood counts get worse for a few weeks immediately after starting treatment, although some patients find their blood counts begin to improve within just two weeks.
It typically takes six months to figure out whether this therapy is useful. Common criteria for treatment success include:
If it is well-tolerated, patients usually take the hormone for 12 to 18 months. An attempt may be made then to end the treatment, but most patients discover that they need to continue taking the drug for it to be successful. These patients often continue taking this drug indefinitely, until either the disease becomes resistant to this hormone, or the body produces an immune system response that limits the drug's ability to function. A few patients are able to achieve a sustained clinical remission after taking this drug for six months to one year. This may be more likely when IFN-alpha has been initiated shortly 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 for decreased blood flow to the placenta.
Interferon-alpha works by sensitizing the hairy cells to the killing effect of the immune system hormone TNF-alpha, whose production it promotes. IFN-alpha works best on classic hairy cells that are not protectively adhered to vitronectin or fibronectin, which suggests that patients who encounter less fibrous tissue in their bone marrow biopsies may be more likely to respond to Interferon-alpha therapy. It also explains why non-adhered hairy cells, such as those in the bloodstream, disappear during IFN-alpha treatment well before reductions are seen in adhered hairy cells, such as those in the bone marrow and spleen.
can produce long-term remissions in patients whose spleens seem to be heavily involved, but its success rate is noticeably lower than cladribine or pentostatin. Splenectomies are also performed for patients whose persistently enlarged spleens cause significant discomfort or in patients whose persistently low platelet counts suggest Idiopathic thrombocytopenic purpura
.
Bone marrow transplant
s are usually shunned in this highly treatable disease because of the inherent risks in the procedure. They may be considered for refractory cases in younger, otherwise healthy individuals. "Mini-transplants" are possible.
Patients 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 may also receive a hormone to stimulate production of red blood cells. These treatments may be medically necessary
, but do not kill the hairy cells.
Patients with low neutrophil counts may be given filgrastim
or a similar hormone to stimulate production of white blood cells. However, a 1999 study indicates that routine administration of this expensive injected drug has no practical value for HCL patients after cladribine administration. In this study, patients who received filgrastim were just as likely to experience a high fever and to be admitted to the hospital as those who did not, even though the drug artificially inflated their white blood cell counts. This study leaves open the possibility that filgrastim may still be appropriate for patients who have symptoms of infection, or at times other than shortly after cladribine treatment.
Although hairy cells are technically long-lived, instead of rapidly dividing, some late-stage patients are treated with broad-spectrum chemotherapy agents such as methotrexate
that are effective at killing rapidly dividing cells. This is not typically attempted unless all other options have been exhausted and it is typically unsuccessful.
As with B-cell chronic lymphocytic leukemia, mutations in the IGHV on hairy cells are associated with better responses to initial treatments and with prolonged survival.
How soon after treatment a patient feels "normal" again depends on several factors, including:
Accurately measuring survival for patients with the variant form of the disease (HCL-V) is complicated by the relatively high median age (70 years old) at diagnosis. However, HCL-V patients routinely survive for more than 10 years, and younger patients can likely expect a long life.
Worldwide, approximately 300 HCL patients per year are expected to die. Some of these patients were diagnosed with HCL due to a serious illness that prevented them from receiving initial treatment in time; many others died after living a normal lifespan and experiencing years of good control of the disease. Perhaps as many as five out of six HCL patients die from some other cause.
People in remission need regular follow-up examinations after their treatment is over. Most physicians insist on seeing patients at least once a year for the rest of the patient's life, and getting blood counts about twice a year. Regular follow-up care ensures that patients are carefully monitored, any changes in health are discussed, and new or recurrent cancer 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 at a slightly higher than average risk for developing a second kind of cancer, such as colon cancer or lung cancer, at some point during their lives (including before their HCL diagnosis). This appears to relate best to the number of hairy cells, and not to different forms of treatment. On average, patients might reasonably expect to have as much as double the risk of developing another cancer, with a peak about two years after HCL diagnosis and falling steadily after that, assuming that the HCL was successfully treated. Aggressive surveillance and prevention efforts are generally warranted, although the lifetime odds of developing a second cancer after HCL diagnosis are still less than 50%.
There is also a higher risk of developing an autoimmune disease
. Autoimmune diseases may also go into remission after treatment of HCL.
Because the disease is rare, routine screening is not cost-effective.
is approximately 3 cases per 1,000,000 men each year, and 0.6 cases per 1,000,000 women each year.
Most patients are white males over the age of 50, although it has been diagnosed in at least one teenager. It is less common in people of African and Asian descent compared to people of European descent.
It does not appear to be hereditary, although occasional familial cases that suggest a predisposition have been reported, usually showing a common Human Leukocyte Antigen
(HLA) type.
Three immunotoxin drugs are in Phase II trials at the NIH's National Cancer Institute
in the U.S.: BL22, HA22 and LMB-2. All of these protein-based drugs combine part of an anti-B cell antibody with a bacterial toxin to kill the cells on internalization. BL22 and HA22 attack a common protein called CD22, which is present on hairy cells and healthy B cells. LMB-2 attacks a protein called CD25, which is not present in HCL-variant, so LMB-2 is only useful for patients with HCL-classic or the Japanese variant. All three of these therapies are available only at the National Cancer Institute in Bethesda, Maryland, USA. While initial results are generally favorable, it is likely to be a number of years before these drugs are available on the market.
Other clinical trials are studying the effectiveness of cladribine followed by rituximab in eliminating residual hairy cells
that remain after treatment by cladribine or pentostatin. It is not currently known if the elimination of such residual cells will result in more durable remissions.
The major remaining research questions are identifying the cause of HCL and determining what prevents hairy cells from maturing normally.
Hematological malignancy
Hematological malignancies are the types of cancer that affect blood, bone marrow, and lymph nodes. As the three are intimately connected through the immune system, a disease affecting one of the three will often affect the others as well: although lymphoma is technically a disease of the lymph...
characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia. Hairy cell leukemia makes up approximately 2% of all leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
s, with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.
Hairy cell leukemia was originally described as histiocytic leukemia, malignant reticulosis, or lymphoid myelofibrosis in publications dating back to the 1920s. The disease was formally named leukemic reticuloendotheliosis and its characterization significantly advanced by Bertha Bouroncle and colleagues at The Ohio State University College of Medicine
OSU College of Medicine and Public Health
The Ohio State University College of Medicine is the medical school at The Ohio State University and is located in Columbus, Ohio. The college is nationally recognized as a top institution in both education and research, as reflected by rankings in U.S. News & World Report...
in 1958. Its common name, which was coined in 1966, is derived from the "hairy" appearance of the malignant B cells under a microscope.
Classification
When not further specified, the "classic" form is often implied. However, two variants have been described: Hairy cell leukemia-variant, which usually is diagnosed in men, and a Japanese variant. The non-Japanese variant is more difficult to treat than either 'classic' HCL or the Japanese variant HCL.Hairy cell leukemia-variant
Hairy cell leukemia-variant, or HCL-V, is usually described as a prolymphocytic variant of hairy cell leukemia. It was first formally described in 1980 by a paper from the University of Cambridge's Hayhoe lab. About 10% of HCL patients have this variant form of the disease, representing about 60-75 new HCL-V patients each year in the U.S. While classic HCL primarily affects men, HCL-V is somewhat more evenly divided between males and females. While the disease can appear at any age, the median age at diagnosis is over 70.Similar to B-PLL in Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
, HCL-V is a more aggressive disease. It is less likely to be treated successfully than classic HCL and remissions tend to be shorter. Many treatment approaches, such as Interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
-alpha, CHOP and common alkylating agents like cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
provide very little benefit. Pentostatin and cladribine provide some benefit to many HCL-V patients, but with shorter remissions and lower response rates compared to classic HCL. More than half of patients respond partially to splenectomy.
In terms of B cell development, the prolymphocytes are less developed than lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
cells or plasma cells, but are still more developed than their lymphoblastic precursors.
HCL-V differs from classic HCL principally in these respects:
- High white blood cell counts, sometimes in excess of 100,000 cells per microliter;
- More aggressive course of disease that requires more frequent treatment;
- Cells with an unusually large nucleolus for their size;
- Little excess fibronectinFibronectinFibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
(which is produced by classic hairy cells) to interfere with bone marrow biopsies; and - Low or no expression of CD25CD25CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
(also called the Interleukin-2 [IL-2] receptor alpha chain or p55) on cell surfaces.
The lack of CD25, which is part of the receptor for a key immunoregulating hormone, may explain why HCL-V cases are normally resistant to treatment by immune system hormones.
HCL-V, which has a high proportion of hairy cells without a functional p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
tumor suppressor gene, is somewhat more likely to transform into a higher-grade disease, with Daniel Catovsky suggesting a typical transformation rate of 5% in the U.K., which is similar to the Richter's transformation
Richter's transformation
Richter's transformation, or Richter's syndrome is a complication of B cell chronic lymphocytic leukemia or hairy cell leukemia in which the leukemia changes into a fast-growing diffuse large B cell lymphoma. There is also a less common variant in which the CLL changes into a Hodgkin's lymphoma...
rate for SLVL and CLL and reporting 6% in one group of patients. Among HCL-V patients, the most aggressive cases normally have the least amount of p53 gene activity. Hairy cells without the p53 gene tend, over time, to displace the less aggressive p53+ hairy cells.
Hairy cell leukemia-Japanese variant
Hairy cell leukemia-Japanese variant or HCL-J. There is also a Japanese variant, which is more easily treated.Treatment with cladribine
Cladribine
Cladribine is a drug used to treat hairy cell leukemia and multiple sclerosis. Its chemical name is 2-chlorodeoxyadenosine ....
has been reported.
Symptoms
In hairy cell leukemia, the "hairy cells" (malignant B lymphocytes) accumulate in the bone marrow, interfering with the production of normal white blood cells, red blood cells, and platelets. Consequently, patients may develop infections related to low white blood cell countNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
and fatigue due to a lack of red blood cells, or easy bleeding due to a low platelet count
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
. Leukemic cells may gather in the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
and cause it to swell; this can have the side effect of making the person feel full even when he or she has not eaten much.
Hairy cell leukemia is commonly diagnosed after a routine blood count shows unexpectedly low numbers of one or more kinds of normal blood cells, or after unexplained bruises or recurrent infections in an otherwise apparently healthy patient.
Platelet function may be somewhat impaired in HCL patients, although this does not appear to have any significant practical effect. It may result in somewhat more mild bruises than would otherwise be expected for a given platelet count or a mildly increased bleeding time for a minor cut. It is likely the result of producing slightly abnormal platelets in the overstressed bone marrow tissue.
Patients with a high tumor burden may also have somewhat reduced levels of cholesterol, especially in patients with an enlarged spleen. Cholesterol levels return to more normal values with successful treatment of HCL.
Cause
As with many cancers, the cause of hairy cell leukemia is unknown. Exposure to tobacco smoke, ionizing radiationIonizing radiation
Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...
, or industrial chemicals (with the possible exception of diesel) does not appear to increase the risk of developing HCL. Farming and gardening appear to increase the risk of HCL in some studies.
Recent studies have identified somatic BRAF V600E mutations in all patients with the classic form of hairy cell leukemia thus sequenced, but in no patients with the variant form..
The U.S. Institute of Medicine
Institute of Medicine
The Institute of Medicine is a not-for-profit, non-governmental American organization founded in 1970, under the congressional charter of the National Academy of Sciences...
(IOM) announced "sufficient evidence" of an association between exposure to herbicides and later development of chronic B-cell leukemias and lymphomas in general. The IOM report emphasized that neither animal nor human studies indicate an association of herbicides with HCL specifically. However, the IOM extrapolated data from chronic lymphocytic leukemia and non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
to conclude that HCL and other rare B-cell neoplasms may share this risk factor. As a result of the IOM report, the U.S. Department of Veterans Affairs
United States Department of Veterans Affairs
The United States Department of Veterans Affairs is a government-run military veteran benefit system with Cabinet-level status. It is the United States government’s second largest department, after the United States Department of Defense...
considers HCL an illnesses presumed to be a service-related disability (see Agent Orange
Agent Orange
Agent Orange is the code name for one of the herbicides and defoliants used by the U.S. military as part of its herbicidal warfare program, Operation Ranch Hand, during the Vietnam War from 1961 to 1971. Vietnam estimates 400,000 people were killed or maimed, and 500,000 children born with birth...
).
Human T-lymphotropic virus 2
Human T-lymphotropic virus 2
A virus closely related to HTLV-I, Human T-lymphotropic virus 2 shares approximately 70% genomic homology with HTLV-I....
(HTLV-2) has been isolated in a small number of patients with the variant form of HCL. In the 1980s, HTLV-2 was identified in a patient with a T-cell lymphoproliferative disease; this patient later developed hairy cell leukemia (a B cell disease), but HTLV-2 was not found in the hairy cell clones. There is no evidence that HTLV-II causes any sort of hematological malignancy, including HCL.
Diagnosis
The diagnosis of HCL may be suggested by abnormal results on a complete blood countComplete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
(CBC), but additional testing is necessary to confirm the diagnosis. A CBC normally shows low counts for white blood cells, red blood cells, and platelets in HCL patients. However, if large numbers of hairy cells are in the blood stream, then normal or even high lymphocyte counts
Lymphocytosis
Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood, usually detected when a complete blood count is routinely obtained. Lymphocytes normally represent 20 to 40% of circulating white blood cells...
may be found.
On physical exam, 80–90% of patients have an enlarged spleen
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, which can be massive. This is less likely among patients who are diagnosed at an early stage. Peripheral lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
(enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on computed tomography
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(CT) scans.
The most important lab finding is the presence of hairy cells in the bloodstream. Hairy cells are abnormal white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s with hair-like projections of cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
; they can be seen by examining a blood smear or bone marrow biopsy
Bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
specimen. The blood film examination is done by staining the blood cells with Wright's stain and looking at them under a microscope
Microscope
A microscope is an instrument used to see objects that are too small for the naked eye. The science of investigating small objects using such an instrument is called microscopy...
. Hairy cells are visible in this test in about 85% of cases.
Most patients require a bone marrow biopsy for final diagnosis. The bone marrow biopsy is used both to confirm the presence of HCL and also the absence of any additional diseases, such as Splenic marginal zone lymphoma
Splenic marginal zone lymphoma
Splenic marginal zone lymphoma is a lymphoma made up of B-cells that replace the normal architecture of the white pulp of the spleen. The neoplastic cells are both small lymphocytes and larger, transformed blasts, and they invade the mantle zone of splenic follicles and erode the marginal zone,...
or B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia is a more aggressive, but still treatable, form of leukemia. The malignant B cells are larger than average. The name is commonly abbreviated B-PLL.It can involve deletions from chromosome 11 and chromosome 13....
. The diagnosis can be confirmed by viewing the cells with a special stain known as TRAP (tartrate resistant acid phosphatase
Tartrate resistant acid phosphatase
Tartrate-resistant acid phosphatase or acid phosphatase 5, tartrate resistant is a glycosylated monomeric metalloenzyme expressed in mammals. It has a molecular weight of approximately 35kDa, a basic isoelectric point , and optimal activity in acidic conditions. TRAP is synthesized as latent...
).
It is also possible to definitively diagnose hairy cell leukemia through flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
on blood or bone marrow. The hairy cells are larger than normal and positive for CD19
CD19
B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
, CD20
CD20
B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
, CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
, CD11c
CD11c
CD11c, also known as Integrin, alpha X , is a human gene.CD11c is a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst;...
, CD25
CD25
CD25 is the alpha chain of the IL-2 receptor. It is a type I transmembrane protein present on activated T cells, activated B cells, some thymocytes, myeloid precursors, and oligodendrocytes that associates with CD122 to form a heterodimer that can act as a high-affinity receptor for IL-2.CD25 is...
, CD103, and FMC7. (CD103, CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
, and CD11c
CD11c
CD11c, also known as Integrin, alpha X , is a human gene.CD11c is a type I transmembrane protein found at high levels on most human dendritic cells, but also on monocytes, macrophages, neutrophils, and some B cells that induces cellular activation and helps trigger neutrophil respiratory burst;...
are strongly expressed.)
Hairy cell leukemia-variant (HCL-V), which shares some characteristics with B cell prolymphocytic leukemia (B-PLL), does not show CD25 (also called the Interleukin-2 receptor, alpha). As this is relatively new and expensive technology, its adoption by physicians is not uniform, despite the advantages of comfort, simplicity, and safety for the patient when compared to a bone marrow biopsy. The presence of additional lymphoproliferative diseases is easily checked during a flow cytometry test, where they characteristically show different results.
The differential diagnoses include: several kinds of anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, including myelophthisis
Myelophthisis
Myelophthisic anemia is a severe kind of anemia found in some people with diseases that affect the bone marrow. Myelophythisis refers to the displacement of hemopoietic bone-marrow tissue into the peripheral blood, either by fibrosis, tumors or granulomas.-Causes:Myelophythisis can occur in the...
and aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
, and most kinds of blood neoplasms, including hypoplastic myelodysplastic syndrome
Myelodysplastic syndrome
The myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
, atypical chronic lymphocytic leukemia, B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia is a more aggressive, but still treatable, form of leukemia. The malignant B cells are larger than average. The name is commonly abbreviated B-PLL.It can involve deletions from chromosome 11 and chromosome 13....
, or idiopathic myelofibrosis
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
.Table 4. Phenotypic differential diagnosis of hairy cell leukemia]}}
Pathophysiology
PancytopeniaPancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
in HCL is caused primarily by marrow failure and splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
. Bone marrow failure is caused by the accumulation of hairy cells and reticulin fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
in the bone marrow, as well as by the detrimental effects of dysregulated cytokine production. Splenomegaly reduces blood counts through sequestration, marginalization, and destruction of healthy blood cells inside the spleen.
Hairy cells are nearly mature B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s, which are activated clonal cells with signs of VH gene differentiation. They may be related to pre-plasma marginal zone
Marginal zone
The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen. A marginal zone also exists in lymph nodes.-Composition and markers:It is composed of cells derived...
B cells or memory cells.
Cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
production is disturbed in HCL. Hairy cells produce and thrive on 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 an immune system protein called Interleukin-2 receptor (IL-2R). In HCL-V, only part of this receptor is expressed. As a result, disease status can be monitored by measuring changes in the amount of IL-2R in the blood serum. The level increases as hairy cells proliferate, and decreases when they are killed. Although uncommonly used in North America and northern Europe, this test correlates better with disease status and predicts relapse more accurately than any other test.
Hairy cells respond to normal production of some cytokines by T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s with increased growth. Treatment with Interferon-alpha suppresses the production of this pro-growth cytokine from T cells. A low level of T cells, which is commonly seen after treatment with cladribine
Cladribine
Cladribine is a drug used to treat hairy cell leukemia and multiple sclerosis. Its chemical name is 2-chlorodeoxyadenosine ....
or pentostatin
Pentostatin
Pentostatin is an anticancer chemotherapeutic drug.-Mechanism:It is classified as a purine analog, which is a type of antimetabolite....
, and the consequent reduction of these cytokines, is also associated with reduced levels of hairy cells.
In June 2011, E Tiacci et al
discovered that 100% of hairy-cell leukaemia samples analysed had the oncogenic BRAF
BRAF
BRAF can refer to* Baton Rouge Area Foundation* The BRAF gene...
mutation V600E, and proposed that this is the disease's driver mutation. Until this point, only a few genomic
Comparative genomic hybridization
Comparative genomic hybridization or Chromosomal Microarray Analysis is a molecular-cytogenetic method for the analysis of copy number changes in the DNA content of a given subject's DNA and often in tumor cells....
imbalances had been found in the hairy cells, such as trisomy
Trisomy
A trisomy is a type of polysomy in which there are three copies, instead of the normal two, of a particular chromosome. A trisomy is a type of aneuploidy .-Description and causes:...
5 had been found. The expression of genes
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
is also dysregulated in a complex and specific pattern. The cells underexpress 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 yet been demonstrated that any of these changes have any practical significance to the patient.
Treatment
Several treatments are available, and successful control of the disease is common.Not everyone needs treatment. Treatment is usually given when the symptoms of the disease interfere with the patient's everyday life, or when white blood cell or platelet counts decline to dangerously low levels, such as an absolute neutrophil count
Absolute neutrophil count
Absolute neutrophil count is a measure of the number of neutrophil granulocytes present in the blood...
below one thousand cells per microliter (1.0 K/uL). Not all patients need treatment immediately upon diagnosis, and about 10% of patients will never need treatment.
Treatment delays are less important than in solid tumors. Unlike most cancers, treatment success does not depend on treating the disease at an early stage. Because delays do not affect treatment success, there are no standards for how quickly a patient should receive treatment. However, waiting too long can cause its own problems, such as an infection that might have been avoided by proper treatment to restore immune system function. Also, having a higher number of hairy cells at the time of treatment can make certain side effects somewhat worse, as some side effects are primarily caused by the body's natural response to the dying hairy cells. This can result in the hospitalization of a patient whose treatment would otherwise be carried out entirely at the hematologist's office.
Single-drug treatment is typical. Unlike most cancers, only one drug is normally given to a patient at a time. While monotherapy is normal, combination therapy—typically using one first-line therapy and one second-line therapy—is being studied in current clinical trials and is used more frequently for refractory cases. Combining rituximab with cladribine or pentostatin may or may not produce any practical benefit to the patient. Combination therapy is almost never used with a new patient. Because the success rates with purine analog monotherapy are already so high, the additional benefit from immediate treatment with a second drug in a treatment-naïve patient is assumed to be very low. For example, one round of either cladribine or pentostatin gives the median first-time patient a decade-long remission; the addition of rituximab, which gives the median patient only three or four years, might provide no additional value for this easily treated patient. In a more difficult case, however, the benefit from the first drug may be substantially reduced and therefore a combination may provide some benefit.
First-line therapy: purine analog chemotherapy
CladribineCladribine
Cladribine is a drug used to treat hairy cell leukemia and multiple sclerosis. Its chemical name is 2-chlorodeoxyadenosine ....
(2CDA) and pentostatin
Pentostatin
Pentostatin is an anticancer chemotherapeutic drug.-Mechanism:It is classified as a purine analog, which is a type of antimetabolite....
(DCF) are the two most common first-line therapies. They both belong to a class of medications called purine analogs, which have mild side effects compared to traditional chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
regimens.
Cladribine can be administered by injection under the skin, by infusion over a couple of hours into a vein, or by a pump worn by the patient that provides a slow drip into a vein, 24 hours a day for 7 days. Most patients receive cladribine by IV infusion once a day for five to seven days, but more patients are being given the option of taking this drug once a week for six weeks. The different dosing schedules used with cladribine are approximately equally effective and equally safe.
Relatively few patients have significant side effects other than fatigue and a high fever caused by the cancer cells dying, although complications like infection and acute kidney failure have been seen.
Pentostatin is chemically similar to cladribine, and has a similar success rate and side effect profile, but it is always given over a much longer period of time, usually one dose by IV infusion every two weeks for three to six months.
During the weeks following treatment the patient's immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
is severely weakened, but their bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
will begin to produce normal blood cells again. Treatment often results in long-term remission. About 85% of patients achieve a complete response from treatment with either cladribine or pentostatin, and another 10% receive some benefit from these drugs, although there is no permanent cure for this disease. If the cancer cells return, the treatment may be repeated and should again result in remission, although the odds of success decline with repeated treatment. Remission lengths vary significantly, from one year to more than twenty years. The median patient can expect a treatment-free interval of about ten years.
It does not seem to matter which drug a patient receives. A patient who is not successfully treated with one of these two drugs has a reduced chance of being successfully treated with the other. However, there are other options.
Second-line therapy: immunotherapy
If a patient is resistant to either cladribine or pentostatin, then second-line therapy is pursued.Monoclonal antibodies The most common treatment for cladribine-resistant disease is infusing monoclonal antibodies that destroy cancerous B cells. Rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
is by far the most commonly used. Most patients receive one IV infusion over several hours each week for four to eight weeks. A 2003 publication found two partial and ten complete responses out of 15 patients with relapsed disease, for a total of 80% responding. The median patient (including non-responders) did not require further treatment for more than three years. This eight-dose study had a higher response rate than a four-dose study at Scripps, which achieved only 25% response rate. Rituximab has successfully induced a complete response in Hairy Cell-Variant.
Rituximab's major side effect is serum sickness, commonly described as an "allergic reaction", which can be severe, especially on the first infusion. Serum sickness is primarily caused by the antibodies clumping during infusion and triggering the complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
cascade. Although most patients find that side effects are adequately controlled by anti-allergy drugs, some severe, and even fatal, reactions have occurred. Consequently, the first dose is always given in a hospital setting, although subsequent infusions may be given in a physician's office. Remissions are usually shorter than with the preferred first-line drugs, but hematologic remissions of several years' duration are not uncommon.
Other B cell-destroying monoclonal antibodies such as Alemtuzumab
Alemtuzumab
Alemtuzumab is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia , cutaneous T-cell lymphoma and T-cell lymphoma...
, Ibritumomab tiuxetan
Ibritumomab tiuxetan
Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for some forms of B cell non-Hodgkin's lymphoma, a lymphoproliferative disorder and thus affects the lymphatic system...
and I-131 Tositumomab
Tositumomab
Tositumomab is a drug for the treatment of follicular lymphoma. It is a IgG2a anti-CD20 monoclonal antibody derived from immortalized mouse cells....
may be considered for refractory cases.
Interferon-alpha Interferon-alpha is an immune system hormone that is very helpful to a relatively small number of patients, and somewhat helpful to most patients. In about 65% of patients, the drug helps stabilize the disease or produce a slow, minor improvement for a partial response.
The typical dosing schedule injects at least 3 million units of Interferon-alpha (not pegylated versions) three times a week, although the original protocol began with six months of daily injections.
Some patients tolerate IFN-alpha very well after the first couple of weeks, while others find that its characteristic flu-like symptoms persist. About 10% of patients develop a level of depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
. It is possible that, by maintaining a steadier level of the hormone in the body, that daily injections might cause fewer side effects in selected patients. Drinking at least two liters of water each day, while avoiding caffeine and alcohol, can reduce many of the side effects.
A drop in blood counts is usually seen during the first one to two months of treatment. Most patients find that their blood counts get worse for a few weeks immediately after starting treatment, although some patients find their blood counts begin to improve within just two weeks.
It typically takes six months to figure out whether this therapy is useful. Common criteria for treatment success include:
- normalization of hemoglobin levels (above 12.0 g/dL),
- a normal or somewhat low platelet count (above 100 K/µL), and
- a normal or somewhat low absolute neutrophil count (above 1.5 K/µL).
If it is well-tolerated, patients usually take the hormone for 12 to 18 months. An attempt may be made then to end the treatment, but most patients discover that they need to continue taking the drug for it to be successful. These patients often continue taking this drug indefinitely, until either the disease becomes resistant to this hormone, or the body produces an immune system response that limits the drug's ability to function. A few patients are able to achieve a sustained clinical remission after taking this drug for six months to one year. This may be more likely when IFN-alpha has been initiated shortly 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 for decreased blood flow to the placenta.
Interferon-alpha works by sensitizing the hairy cells to the killing effect of the immune system hormone TNF-alpha, whose production it promotes. IFN-alpha works best on classic hairy cells that are not protectively adhered to vitronectin or fibronectin, which suggests that patients who encounter less fibrous tissue in their bone marrow biopsies may be more likely to respond to Interferon-alpha therapy. It also explains why non-adhered hairy cells, such as those in the bloodstream, disappear during IFN-alpha treatment well before reductions are seen in adhered hairy cells, such as those in the bone marrow and spleen.
Other treatment options
SplenectomySplenectomy
A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...
can produce long-term remissions in patients whose spleens seem to be heavily involved, but its success rate is noticeably lower than cladribine or pentostatin. Splenectomies are also performed for patients whose persistently enlarged spleens cause significant discomfort or in patients whose persistently low platelet counts suggest Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura
Idiopathic thrombocytopenic purpura is the condition of having an abnormally low platelet count of no known cause . As most incidents of ITP appear to be related to the production of antibodies against platelets, immune thrombocytopenic purpura or immune thrombocytopenia are terms also used to...
.
Bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...
s are usually shunned in this highly treatable disease because of the inherent risks in the procedure. They may be considered for refractory cases in younger, otherwise healthy individuals. "Mini-transplants" are possible.
Patients with anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
or thrombocytopenia
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
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
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
. Patients may also receive a hormone to stimulate production of red blood cells. These treatments may be medically necessary
Medical necessity
Medical necessity is a United States legal doctrine, related to activities which may be justified as reasonable, necessary, and/or appropriate, based on evidence-based clinical standards of care. Other countries may have medical doctrines or legal rules covering broadly similar grounds...
, but do not kill the hairy cells.
Patients with low neutrophil counts may be given filgrastim
Filgrastim
Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. ...
or a similar hormone to stimulate production of white blood cells. However, a 1999 study indicates that routine administration of this expensive injected drug has no practical value for HCL patients after cladribine administration. In this study, patients who received filgrastim were just as likely to experience a high fever and to be admitted to the hospital as those who did not, even though the drug artificially inflated their white blood cell counts. This study leaves open the possibility that filgrastim may still be appropriate for patients who have symptoms of infection, or at times other than shortly after cladribine treatment.
Although hairy cells are technically long-lived, instead of rapidly dividing, some late-stage patients are treated with broad-spectrum chemotherapy agents such as methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
that are effective at killing rapidly dividing cells. This is not typically attempted unless all other options have been exhausted and it is typically unsuccessful.
Treatment success
More than 95% of new patients are treated well or at least adequately by cladribine or pentostatin. A majority of new patients can expect a disease-free remission time span of about ten years, or sometimes much longer after taking one of these drugs just once. If re-treatment is necessary in the future, the drugs are normally effective again, although the average length of remission is somewhat shorter in subsequent treatments.As with B-cell chronic lymphocytic leukemia, mutations in the IGHV on hairy cells are associated with better responses to initial treatments and with prolonged survival.
How soon after treatment a patient feels "normal" again depends on several factors, including:
- how advanced the disease was at the time of treatment;
- the patient's underlying health status;
- whether the patient had a "complete response" or only a partial response to the treatment;
- whether the patient experienced any of the rare, but serious side effects such as kidney failure;
- how aggressive the individual's disease is;
- whether the patient is experiencing unusual psychological trauma from the "cancer" diagnosis; and
- how the patient perceived his or her pre-treatment energy level and daily functioning.
Lifespan
With appropriate treatment, the overall projected lifespan for patients is normal or near-normal. In all patients, the first two years after diagnosis have the highest risk for fatal outcome; generally, surviving five years predicts good control of the disease. After five years' clinical remission, patients with normal blood counts can often qualify for private life insurance with some companies.Accurately measuring survival for patients with the variant form of the disease (HCL-V) is complicated by the relatively high median age (70 years old) at diagnosis. However, HCL-V patients routinely survive for more than 10 years, and younger patients can likely expect a long life.
Worldwide, approximately 300 HCL patients per year are expected to die. Some of these patients were diagnosed with HCL due to a serious illness that prevented them from receiving initial treatment in time; many others died after living a normal lifespan and experiencing years of good control of the disease. Perhaps as many as five out of six HCL patients die from some other cause.
Follow-up care
Despite decade-long remissions and years of living very normal lives after treatment, hairy cell leukemia is officially considered an incurable disease. While survivors of solid tumors are commonly declared to be permanently cured after two, three, or five years, people who have hairy cell leukemia are never considered 'cured'. Relapses of HCL have happened even after more than twenty years of continuous remission. Patients will require lifelong monitoring and should be aware that the disease can recur even after decades of good health.People in remission need regular follow-up examinations after their treatment is over. Most physicians insist on seeing patients at least once a year for the rest of the patient's life, and getting blood counts about twice a year. Regular follow-up care ensures that patients are carefully monitored, any changes in health are discussed, and new or recurrent cancer 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 at a slightly higher than average risk for developing a second kind of cancer, such as colon cancer or lung cancer, at some point during their lives (including before their HCL diagnosis). This appears to relate best to the number of hairy cells, and not to different forms of treatment. On average, patients might reasonably expect to have as much as double the risk of developing another cancer, with a peak about two years after HCL diagnosis and falling steadily after that, assuming that the HCL was successfully treated. Aggressive surveillance and prevention efforts are generally warranted, although the lifetime odds of developing a second cancer after HCL diagnosis are still less than 50%.
There is also a higher risk of developing an autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
. Autoimmune diseases may also go into remission after treatment of HCL.
Prevention/Screening
Because the cause is unknown, no effective preventive measures can be taken.Because the disease is rare, routine screening is not cost-effective.
Epidemiology
This disease is rare, with fewer than 1 in 10,000 people being diagnosed with HCL during their lives. Men are four to five times more likely to develop hairy cell leukemia than women. In the United States, the annual incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
is approximately 3 cases per 1,000,000 men each year, and 0.6 cases per 1,000,000 women each year.
Most patients are white males over the age of 50, although it has been diagnosed in at least one teenager. It is less common in people of African and Asian descent compared to people of European descent.
It does not appear to be hereditary, although occasional familial cases that suggest a predisposition have been reported, usually showing a common Human Leukocyte Antigen
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
(HLA) type.
Research directions
The Hairy Cell Leukemia Consortium was founded in 2008 to address researchers' concerns about the long-term future of research on the disease. Partly because existing treatments are so successful, the field has attracted very few new researchers.Three immunotoxin drugs are in Phase II trials at the NIH's National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
in the U.S.: BL22, HA22 and LMB-2. All of these protein-based drugs combine part of an anti-B cell antibody with a bacterial toxin to kill the cells on internalization. BL22 and HA22 attack a common protein called CD22, which is present on hairy cells and healthy B cells. LMB-2 attacks a protein called CD25, which is not present in HCL-variant, so LMB-2 is only useful for patients with HCL-classic or the Japanese variant. All three of these therapies are available only at the National Cancer Institute in Bethesda, Maryland, USA. While initial results are generally favorable, it is likely to be a number of years before these drugs are available on the market.
Other clinical trials are studying the effectiveness of cladribine followed by rituximab in eliminating residual hairy cells
Minimal residual disease
Minimal residual disease is the name given, to small numbers of leukaemic cells that remain in the patient during treatment, or after treatment when the patient is in remission . It is the major cause of relapse in cancer and leukaemia. Up until a decade ago none of the tests used to assess/detect...
that remain after treatment by cladribine or pentostatin. It is not currently known if the elimination of such residual cells will result in more durable remissions.
The major remaining research questions are identifying the cause of HCL and determining what prevents hairy cells from maturing normally.
External links
- About HCL at the US National Cancer InstituteNational Cancer InstituteThe National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
- About HCL by the Hairy Cell Leukemia Consortium
- History of HCL and the Godmother of HCL
- Clinically reviewed Hairy cell leukaemia information for patients, from Cancer Research UKCancer Research UKCancer Research UK is a cancer research and awareness charity in the United Kingdom, formed on 4 February 2002 by the merger of The Cancer Research Campaign and the Imperial Cancer Research Fund. Its aim is to reduce the number of deaths from cancer. As the world's largest independent cancer...