Hairy cell leukemia is an uncommon
hematological malignancy
Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all ...
characterized by an accumulation of abnormal
B lymphocyte
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s. It is usually classified as a subtype of
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
(CLL). Hairy cell leukemia makes up about 2% of all
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ' ...
s, with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.
Hairy cell leukemia (HCL) 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 was significantly advanced by
Bertha Bouroncle
Bertha A. Bouroncle Pereny (September 10, 1919 – August 13, 2013) was a Peruvian-American hematologist. After completing medical school in Peru, Bouroncle came to the United States for her postgraduate medical training. A longtime member of the ...
and colleagues at the
Ohio State University College of Medicine
The Ohio State University College of Medicine (formerly known as The Ohio State University College of Medicine and Public Health) is the medical school at The Ohio State University and is located in Columbus, Ohio. The college is nationally re ...
in 1958. Its common name, which was coined in 1966, is derived from the "hairy" appearance of the malignant B cells under a microscope.
Signs and symptoms
In HCL, the "hairy cells" (malignant B lymphocytes) accumulate in the bone marrow, interfering with the production of normal
white blood cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
,
red blood cells
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek language, Greek ''erythros'' for "red" and ''k ...
, and
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
. Consequently, patients may develop infections related to
low white blood cell count,
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
and fatigue due to a lack of red blood cells, or easy bleeding due to a
low platelet count
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients and ...
.
Platelet function may be somewhat impaired in HCL patients, although this does not appear to have any significant practical effect.
Patients with a high tumor burden may also have somewhat reduced levels of cholesterol, especially in patients with an enlarged spleen.
Cause
As with many cancers, the cause of HCL is unknown. Exposure to tobacco smoke,
ionizing radiation
Ionizing radiation (or ionising radiation), including nuclear radiation, consists of subatomic particles or electromagnetic waves that have sufficient energy to ionize atoms or molecules by detaching electrons from them. Some particles can travel ...
, or industrial chemicals (with the possible exception of
diesel
Diesel may refer to:
* Diesel engine, an internal combustion engine where ignition is caused by compression
* Diesel fuel, a liquid fuel used in diesel engines
* Diesel locomotive, a railway locomotive in which the prime mover is a diesel engin ...
) does not appear to increase the risk of developing it.
Farming and gardening correlate with an increased risk of HCL development in some studies which does not necessarily imply causation.
A 2011 study identified somatic ''BRAF'' V600E mutations in all 47 HCL patients studied, and no such mutations in the 193 peripheral B-cell lymphomas/leukemias other than HCL.
The U.S.
Institute of Medicine
The National Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM) until 2015, is an American nonprofit, non-governmental organization. The National Academy of Medicine is a part of the National Academies of Sciences, E ...
(IOM) found a correlation which permits an association between exposure to herbicides and later development of chronic B-cell leukemias and lymphomas in general. The IOM report emphasizes 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 (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
to conclude that HCL and other rare B-cell neoplasms may share this risk factor.
Human T-lymphotropic virus 2
A virus closely related to HTLV-I, human T-lymphotropic virus 2 (HTLV-II) shares approximately 70% genomic homology (structural similarity) with HTLV-I. It was discovered by Robert Gallo and colleagues.
HTLV-2 is prevalent among the indigenou ...
(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 HCL, 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.
Pathophysiology
Pancytopenia
Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.).
If only two parameters from the complete blood coun ...
in HCL is caused primarily by marrow failure and
splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulating ...
. Bone-marrow failure is caused by the accumulation of hairy cells and reticulin
fibrosis
Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of perma ...
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 cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or ...
s, which are activated clonal cells with signs of VH gene differentiation.
They may be related to pre-plasma
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. (Some sources consider it to be the part of red pulp which borders on the white pulp, while other sources consider it to ...
B cells
or
memory cells.
Cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
production is disturbed in HCL. Hairy cells produce and thrive on
TNF-alpha
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
.
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
The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2.
Composition
IL-2 binds to the IL-2 receptor, which has ...
(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.
Hairy cells respond to normal production of some cytokines by
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
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, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia.
Cladribine, sold under the brand name Mavenclad, is indicate ...
or
pentostatin
Pentostatin (or deoxycoformycin, trade name Nipent, manufactured by SuperGen) is an anticancer chemotherapeutic drug.
Mechanism
It is classified as a purine analog, which is a type of antimetabolite.
It mimics the nucleoside adenosine and thus in ...
, 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 HCL 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
Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
imbalances had been found in the hairy cells, such as
trisomy
A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes).
Description and causes
Most organisms that reprodu ...
5 had been found.
The
expression of genes
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
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.
Diagnosis
The diagnosis of HCL may be suggested by abnormal results on a
complete blood count
A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cell ...
(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 examination, 80–90% of patients have an
enlarged spleen
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulating ...
, which can be massive.
This is less likely among patients who are diagnosed at an early stage. Peripheral
lymphadenopathy
Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In cli ...
(enlarged lymph nodes) is uncommon (less than 5% of patients), but abdominal lymphadenopathy is a relatively common finding on
computed tomography
A computed tomography scan (CT scan; formerly called computed axial tomography scan or CAT scan) is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers ...
scans.
![Hairy cell leukemia smear 2009-08-20](https://upload.wikimedia.org/wikipedia/commons/e/e4/Hairy_cell_leukemia_smear_2009-08-20.JPG)
The most important laboratory finding is the presence of hairy cells in the bloodstream.
Hairy cells are abnormal white blood cells with hair-like projections of
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
; they can be seen by examining a
blood smear
A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the ...
or
bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of condition ...
specimen. The blood film examination is done by
staining
Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in the ...
the blood cells with
Wright's stain
Wright's stain is a hematologic stain that facilitates the differentiation of blood cell types. It is classically a mixture of eosin (red) and methylene blue dyes. It is used primarily to stain peripheral blood smears, urine samples, and bone marr ...
and looking at them under a
microscope
A microscope () is a laboratory instrument used to examine objects that are too small to be seen by the naked eye. Microscopy is the science of investigating small objects and structures using a microscope. Microscopic means being invisibl ...
. 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 (SMZL) is a type of cancer (specifically 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 l ...
or
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia, referred to as B-PLL, is a rare blood cancer. It is a more aggressive, but still treatable, form of leukemia.
Specifically, B-PLL is a prolymphocytic leukemia (PLL) that affects prolymphocytes – immature forms ...
. The diagnosis can be confirmed by viewing the cells with a special stain known as TRAP (
tartrate resistant acid phosphatase
Tartrate-resistant acid phosphatase (TRAP or TRAPase), also called acid phosphatase 5, tartrate resistant (ACP5), is a glycosylated monomeric metalloprotein enzyme expressed in mammals. It has a molecular weight of approximately 35kDa, a basic iso ...
). More recently, DB44 testing assures more accurate results.
Definitively diagnosing HCL is also possible through
flow cytometry
Flow cytometry (FC) is a technique used to detect and measure physical and chemical characteristics of a population of cells or particles.
In this process, a sample containing cells or particles is suspended in a fluid and injected into the flo ...
on blood or bone marrow. The hairy cells are larger than normal and positive for
CD19
B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In humans, ...
,
CD20
B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity.
In humans CD20 is encoded by the ''MS4A1'' gene.
This gene e ...
,
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. Generally speaking, CD22 is a regulatory molecule that ...
,
CD11c
CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c .
CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alph ...
,
CD25
Interleukin-2 receptor alpha chain (also called CD25) is the human protein encoded by the ''IL2RA'' gene.
The interleukin 2 (IL2) receptor alpha (IL2RA) and beta (IL2RB) chains, together with the common gamma chain (IL2RG), constitute the high-a ...
,
CD103
Integrin, alpha E (ITGAE) also known as CD103 (cluster of differentiation 103) is an integrin protein that in human is encoded by the ''ITGAE'' gene. CD103 binds integrin beta 7 (β7– ITGB7) to form the complete heterodimeric integrin molecule ...
, and
FMC7
B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase (CD45R+, CD117+) and progressively increasing in concentration until maturity.
In humans CD20 is encoded by the ''MS4A1'' gene.
This gene e ...
antigens. (
CD103
Integrin, alpha E (ITGAE) also known as CD103 (cluster of differentiation 103) is an integrin protein that in human is encoded by the ''ITGAE'' gene. CD103 binds integrin beta 7 (β7– ITGB7) to form the complete heterodimeric integrin molecule ...
,
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. Generally speaking, CD22 is a regulatory molecule that ...
, and
CD11c
CD11c, also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX), is a gene that encodes for CD11c .
CD11c is an integrin alpha X chain protein. Integrins are heterodimeric integral membrane proteins composed of an alph ...
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).
The differential diagnoses include several kinds of anemia, including
myelophthisis
Myelophthisic anemia (or myelophthisis) is a severe type of anemia found in some people with diseases that affect the bone marrow. Myelophthisis refers to the displacement of hemopoietic bone-marrow tissue by fibrosis, tumors, or granulomas. The ...
and
aplastic anemia
Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood ...
, and most kinds of blood neoplasms, including hypoplastic
myelodysplastic syndrome
A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
, atypical chronic lymphocytic leukemia,
B-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia, referred to as B-PLL, is a rare blood cancer. It is a more aggressive, but still treatable, form of leukemia.
Specifically, B-PLL is a prolymphocytic leukemia (PLL) that affects prolymphocytes – immature forms ...
, or idiopathic
myelofibrosis
Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. ...
.
Classification
When not further specified, the "classic" form is often implied, but two variants have been described: Hairy cell leukemia-variant and a Japanese variant. The non-Japanese variant is more difficult to treat than either 'classic' HCL or the Japanese HCL.
HCL-V
Hairy cell leukemia-variant (HCL-V) is usually described as a prolymphocytic variant of HCL.
It was first formally described in 1980 by a paper from the University of Cambridge's Hayhoe laboratory.
About 10% of people with HCL have this variant form of the disease, representing about 60-75 new cases of HCL-V each year in the U.S. While classic HCL primarily affects men, HCL-V is 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-cell prolymphocytic leukemia
B-cell prolymphocytic leukemia, referred to as B-PLL, is a rare blood cancer. It is a more aggressive, but still treatable, form of leukemia.
Specifically, B-PLL is a prolymphocytic leukemia (PLL) that affects prolymphocytes – immature forms ...
(B-PLL) in
chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, nigh ...
, HCL-V is a more aggressive disease. Historically, it has been considered less likely to be treated successfully than is classic HCL, and remissions have tended to be shorter. The introduction of combination therapy with concurrent rituximab and cladribine therapy, though, has shown excellent results in early follow-up. As of 2016, this therapy is considered the first-line treatment of choice for many people with HCL-V.
Many older treatment approaches, such as interferon-alpha, the combination chemotherapy regimen "CHOP", and common alkylating agents such as
cyclophosphamide
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
, showed very little benefit.
Pentostatin and cladribine administered as monotherapy (without concurrent rituximab) provide some benefit to many people with HCL-V, but typically induce shorter remission periods and lower response rates than when they are used in classic HCL. More than half of people respond partially to splenectomy.
HCL-V differs from classic HCL principally in these respects:
* Higher
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and de ...
counts, sometimes exceeding 100,000 cells per microliter
* A more aggressive course of disease requiring more frequent treatment
* Hairy cells with an unusually large
nucleolus
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of sig ...
for their size
* Production of little excess
fibronectin
Fibronectin is a high- molecular weight (~500-~600 kDa) glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. Fibronectin also binds to other extracellular matrix proteins such as collage ...
produced by classic hairy cells to interfere with bone marrow biopsies
* Low or no cell-surface expression of CD25 (interleukin-2
L-2receptor alpha chain, or p55).
Low levels of CD25, a part of the receptor for a key immunoregulating hormone, may explain why HCL-V cases are generally much more resistant to treatment by immune-system hormones.
HCL-V, which usually features a high proportion of hairy cells without a functional ''
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
''
tumor suppressor gene
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
, is somewhat more likely to transform into a higher-grade malignancy. A typical transformation rate of 5-6% has been postulated in the UK, similar to the
Richter's transformation
Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation o ...
rate for
splenic lymphoma with villous lymphocytes
Splenic lymphoma with villous lymphocytes is a rare type of lymphoma that involves mature B cells
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity compone ...
(SLVL) and CLL.
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.
Some evidence suggests that a rearrangement of the immunoglobulin gene ''VH4-34'', which is found in about 40% of HCL-V patients and 10% of classic HCL patients, may be a more important poor prognostic factor than variant status, with HCL-V patients without the VH4-34 rearrangement responding about as well as classic HCL patients.
Hairy cell leukemia-Japanese variant
The variant called hairy cell leukemia-Japanese variant, or HCL-J, is more easily treated. Treatment with
cladribine
Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia.
Cladribine, sold under the brand name Mavenclad, is indicate ...
has been reported.
Prevention
Because the cause is unknown, no effective preventive measures can be taken, but the U.S. Institute of Medicine permits an association to exposure to herbicides (atrazine). The U.S. Department of Veterans Affairs also considers it a service disability related to Agent Orange. Because the disease is rare, routine screening is not cost effective.
Treatment
Several treatments are available, and successful control of the disease is common.
* Not everyone needs treatment immediately. 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 (ANC) is a measure of the number of neutrophil granulocytes (also known as polymorphonuclear cells, PMN's, polys, granulocytes, segmented neutrophils or segs) present in the blood. Neutrophils are a type of white blood ce ...
below 1000 cells per microliter (1.0 K/μL). Not all patients need treatment immediately upon diagnosis.
* 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, no standards exist for how quickly a patient should receive treatment. Waiting too long, though, 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, so a combination may provide some benefit.
First-line therapy
Cladribine
Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia.
Cladribine, sold under the brand name Mavenclad, is indicate ...
(2CDA) and
pentostatin
Pentostatin (or deoxycoformycin, trade name Nipent, manufactured by SuperGen) is an anticancer chemotherapeutic drug.
Mechanism
It is classified as a purine analog, which is a type of antimetabolite.
It mimics the nucleoside adenosine and thus in ...
(DCF) are the two most common first-line therapies. They both belong to a class of medications called
purine analog
Purine analogues are antimetabolites that mimic the structure of metabolic purines.
Examples
* Nucleobase analogues
** Thiopurines such as thioguanine are used to treat acute leukemias and remissions in acute granulocytic leukemias.
***Azathioprin ...
s, which have mild side effects compared to traditional
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
regimens.
Cladribine can be administered by injection under the skin, by infusion over a few hours into a vein (inravenous - IV), 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 roughly equally effective and safe. Relatively few patients have significant side effects other than fatigue and a high fever caused by the cancer cells dying, although complications such as 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 3–6 months.
During the weeks following treatment, the patients' immune systems are 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 no permanent cure for this disease is known. 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.
2-Chlorodeoxyadenosine (Cladribine) induced complete responses in patients with hairy cell leukemia resistant to DCF, suggesting a lack of cross-resistance. Also, 2-CdA is not prohibitively toxic in patients intolerant of DCF (Pentostatin).
Second-line therapy
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 is by far the most commonly used. Most patients receive one IV infusion over several hours each week for 4–8 weeks. Two partial and 10 complete responses resulted fromf 15 patients with relapsed disease, for a total of 80% responding. The median patient (including nonresponders) did not require further treatment for more than 3 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
A complement is something that completes something else.
Complement may refer specifically to:
The arts
* Complement (music), an interval that, when added to another, spans an octave
** Aggregate complementation, the separation of pitch-class ...
cascade. Although most patients find that side effects are adequately controlled by antiallergy 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, sold under the brand names Campath and Lemtrada among others, is a medication used to treat chronic lymphocytic leukemia (CLL) and multiple sclerosis. In CLL, it has been used as both a first line and second line treatment. In MS it ...
,
ibritumomab tiuxetan
Ibritumomab tiuxetan (pronounced ), sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for non-Hodgkin's lymphoma. The drug uses the monoclonal mouse IgG1 antibody ibritumomab in conjunction with the chelator ...
and I-131
tositumomab
Tositumomab is a murine monoclonal antibody which targets the CD20 antigen produced in mammalian cell. It was combined with iodine-131 to produce a radiopharmaceutical for unsealed source radiotherapy, Iodine-131 Tositumomab (branded as Bexxar), fo ...
may be considered for refractory cases.
* 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 6 months of daily injections.
Some patients tolerate IFN-alpha very well after the first fw weeks, while others find that its characteristic
flu-like symptoms
Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss o ...
persist. About 10% of patients develop a level of
depression. By maintaining a steadier level of the hormone in the body, daily injections might cause fewer side effects in selected patients. Drinking at least 2 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 1–2 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 2 weeks.
Typically, 6 months are neededto 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. IFN-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.
IFN-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 IFN-alpha therapy. It also explains why unadhered 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 treatments
Splenectomy 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
Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is a type of thrombocytopenic purpura defined as an isolated low platelet count with a normal bone marrow in the absence of oth ...
.
Bone marrow transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...
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. "Minitransplants" are possible.
People with
low numbers of red blood cells or
platelets
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
may also receive red blood cells and platelets through
blood transfusions
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
. Blood transfusions are always irradiated to remove white blood cells and thereby reduce the risk of
graft-versus-host disease
Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.
White blood cells of the donor's immune system which remain wit ...
. Affected people 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.
People with low
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
counts may be given
filgrastim
Filgrastim, sold under the brand name Neupogen among others, is a medication used to treat low neutrophil count. Low neutrophil counts may occur with HIV/AIDS, following chemotherapy or radiation poisoning, or be of an unknown cause. It may ...
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 (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
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.
Prognosis
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 retreatment is necessary in the future, the drugs are normally effective again, although the average length of remission is somewhat shorter in subsequent treatments. There is also the risk of Shingles, and Peripheral Neuropathy after treatment with cladribine.
As with B-cell chronic lymphocytic leukemia, mutations in the
IGHV
Ig heavy chain V-III region VH26 is a protein that in humans is encoded by the ''IGHV@'' gene.
IGHV is the immunoglobulin heavy chain variable region genes; in B-cell neoplasms like chronic lymphocytic leukemia, mutations of IGHV are associated ...
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 in the United States with normal blood counts can often qualify for private life insurance with some US 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.
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.
While most oncologists consider Hairy Cell Leukemia to be incurable, there is some evidence that some patients are in fact cured after treatments. Of the original 358-patient cohort treated with cladribine at the Scripps Clinic, 9 of 19 in continuous CR for a median of 16 years were free of HCL MRD by flow cytometry and IHC. This suggests that the disease of at least some patients may be cured.
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
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
.
Polyarteritis nodosa
Polyarteritis nodosa (PAN) is a systemic necrotizing inflammation of blood vessels (vasculitis) affecting medium-sized muscular arteries, typically involving the arteries of the kidneys and other internal organs but generally sparing the lungs' c ...
has been associated with underlying hairy cell leukemia in certain cases. Autoimmune diseases may also go into remission after treatment of HCL.
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
incidence 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
The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for the regulation of the immune system. The HLA system is also known as the human version of th ...
(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.
In 2013 th
Hairy Cell Leukemia Foundationwas created when the Hairy Cell Leukemia Consortium and the Hairy Cell Leukemia Research Foundation joined. The HCLF is dedicated to improving outcomes for patients by advancing research into the causes and treatment of hairy cell leukemia, as well as by providing educational resources and comfort to all those affected by hairy cell leukemia.
Three immunotoxin drugs have been studied in patients at the
NIH
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
National Cancer Institute
The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
in the U.S.:
BL22,
HA22
Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including ...
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. HA-22, now renamed
moxetumomab pasudotox
Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti- CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, includin ...
, is being studied in patients with relapsed hairy cell leukemia 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 start accepting patients in late 2014, including The Royal Marsden Hospital in London, England.
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.
BRAF mutation has been frequently detected in HCL (Tiacci et al. NEJM 2011) and some patients may respond to Vemurafenib.
The major remaining research questions are identifying the cause of HCL and determining what prevents hairy cells from maturing normally.
References
External links
{{DEFAULTSORT:Hairy Cell Leukemia
Lymphocytic leukemia
Lymphoid-related cutaneous conditions