Hairy Cell Leukemia – Causes, Symptoms, Treatment

Hairy Cell Leukemia (HCL) is a relatively rare chronic B-cell malignancy that involves the bone marrow, spleen, and peripheral blood. The complete blood count may reveal pancytopenia including monocytopenia. The median age at diagnosis is approximately 55. Poor prognostic features, while somewhat variable in the literature, may include age, hemoglobin less than 10  g/dL, platelets less than 100, ANC less than 1000, the presence of lymphadenopathy, and massive splenomegaly. Differential diagnosis includes other B-cell lymphoproliferative disorders, including splenic marginal zone lymphoma. A distinct entity is known as hairy cell leukemia variant (HCL-V), which is biologically unique from HCL also exists. Response to typical HCL in this disease is poor. The variant can be identified by immunophenotypic differences, lack of BRAF mutation, and lack of monocytopenia.[rx][rx] HCL accounts for 2% of all leukemias with approximately 1000 new cases being reported in the United States each year.

Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes.^[rx] It is usually classified as a sub-type of chronic lymphocytic leukemia (CLL). Hairy cell leukemia makes up approximately 2% of all leukemias, with fewer than 2,000 new cases diagnosed annually in North America and Western Europe combined.

Types of Hairy Cell Leukemia

When not further specified, the “classic” form is often implied. However, two variants have been described: Hairy cell leukemia-variant^[rx] 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.^[rx] It was first formally described in 1980 by a paper from the University of Cambridge’s Hayhoe lab.^[rx] 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.^[rx] While the disease can appear at any age, the median age at diagnosis is over 70.^[rx]

Similar to B-cell prolymphocytic leukemia (“B-PLL”) in Chronic lymphocytic leukemia, 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.

However, the introduction of combination therapy with concurrent rituximab and cladribine therapy has shown excellent results in the early follow-up.^[rx] As of 2016, this therapy is considered the first-line treatment of choice for many people with HCL-V.^[rx]

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

HCL-V differs from classic HCL principally in the following respects:

• Higher white blood cell 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 for their size;
• Production of little excess fibronectin produced by classic hairy cells;^[rx] to interfere with bone marrow biopsies; and
• Low or no cell-surface expression of CD25 (also called the Interleukin-2 [IL-2] receptor alpha chain, or p55).^[rx]

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.^[rx]

HCL-V, which usually features a high proportion of hairy cells without a functional p53 tumor suppressor gene, is somewhat more likely to transform into a higher-grade malignancy. A typical transformation rate of 5%-6% has been postulated in the U.K., similar to the Richter’s transformation rate for SLVL and CLL.^[rx]rx] Among HCL-V patients, the most aggressive cases normally have the least amount of p53 gene activity.^[rx] Hairy cells without the p53 gene tend, over time, to displace the less aggressive p53(+) hairy cells.

There is some evidence suggesting 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, maybe 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.^[rx]

Causes of Hairy Cell Leukemia

The etiology of hairy cell leukemia is not well elucidated. However, previous exposure to various chemicals may play a role in its development. Most cases are postulated to be derived from the V600E BRAF gene mutation of late activated memory B cells.

As with many cancers, the cause of hairy cell leukemia is unknown. Exposure to tobacco smoke, ionizing radiation, or industrial chemicals (with the possible exception of diesel) does not appear to increase the risk of developing HCL.^[rx] Farming and gardening correlate with an increased risk of HCL development in some studies which does not necessarily imply causation.^[rx]

A 2011 study identified somatic BRAF V600E mutations in all 47 hairy cell leukemia (HCL) patients studied, and no such mutations in the 193 peripheral B-cell lymphomas/leukemias other than HCL.^[rx]

The U.S. Institute of Medicine (IOM) sees 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 to conclude that HCL and other rare B-cell neoplasms may share this risk factor.^[rx] As a result of the IOM report, the U.S. Department of Veterans Affairs considers HCL an illness presumed to be a service-related disability.

Human T-lymphotropic virus 2 (HTLV-2) has been isolated in a small number of patients with the variant form of HCL.^[rx] 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.^[rx] There is no evidence that HTLV-II causes any sort of hematological malignancy, including HCL.^[rx]

Symptoms of Hairy Cell Leukemia

These and other signs and symptoms may be caused by hairy cell leukemia or by other conditions. Check with your doctor if you have any of the following:

• Weakness or feeling tired.
• Fever or frequent infections.
• Easy bruising or bleeding.
• Shortness of breath.
• Weight loss for no known reason.
• Pain or a feeling of fullness below the ribs.
• Painless lumps in the neck, underarm, stomach, or groin.

Diagnosis of Hairy Cell Leukemia

The diagnosis of HCL is based on morphological evidence of hairy cells under microscopic examination. The HCL cell is a mononuclear cell that is usually 1 to 2 times the size of a mature lymphocyte. HCL cells can be identified in Romanowsky-stained peripheral blood films from approximately 90% of patients as mononuclear cells that are usually 1 to 2 times the size of a mature lymphocyte. The nuclei are most commonly ovoid but may be round, oval, or horseshoe-shaped. The cytoplasm is variable in amount but usually abundant, pale blue to blue-gray, and occasionally described as “fluffy” or “hairy.” The hairy projections are more easily visualized under the electron microscope.

History and Physical

Affected patients often have non-specific symptoms including fatigue and weakness, as well as symptoms related to cytopenias and splenomegaly. Eighty percent of patients will have significant cytopenias on presentation, with severe pancytopenia in less than 10%. While splenomegaly is a predominant feature, massive, symptomatic splenomegaly is less frequent, perhaps due to earlier detection on routine complete blood count (CBC). Autoimmune thrombocytopenia and hemolytic anemia can occur along with hairy cell leukemia, rarely. Infectious complications are common, due to both the underlying immunosuppression from cytopenias and myelosuppressive therapy.

Evaluation

Diagnosis is achieved by studies on peripheral blood, including flow cytometry and review of the peripheral smear, along with bone marrow biopsy. A “dry tap,” or, inability to perform bone marrow aspiration is frequently encountered with hairy cell leukemia although not with HCL-V. The hairy cell has characteristic-appearing mononuclear cells which are typically large with circumferential hair-like cytoplasmic projections and around, well-defined nucleus. The flow cytometry markers positive in hairy cell leukemia include CD11c, CD25, CD103, and CD123, along with typical B-cell markers such as CD19, CD20, or CD22. The cyclin-d1 expression is usually present, but it is weak or focal (in contrast to mantle cell lymphoma). HCL-V is negative for CD25 and CD123. BRAF-mutation V600E is seen in nearly all cases of classic hairy cell leukemia (although it is not present in HCL-V). CT should be considered to assess the degree of lymphadenopathy.[rx][rx][rx]

Watchful waiting

• Watchful waiting is closely monitoring a patient’s condition, without giving any treatment until signs or symptoms appear or change.

Chemotherapy

• Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated. Cladribine and pentostatin are anticancer drugs commonly used to treat hairy cell leukemia. These drugs may increase the risk of other types of cancer, especially Hodgkin lymphoma and non-Hodgkin lymphoma. Long-term follow up for second cancers is very important.

Immunotherapy

• Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This cancer treatment is a type of biologic therapy.

Targeted therapy

• Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells. Targeted therapies usually cause less harm to normal cells than chemotherapy or radiation therapy do.
• Monoclonal antibody therapy – Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.
  Rituximab is a type of monoclonal antibody that may be used to treat certain patients with hairy cell leukemia.

Treatment of Relapsed or Refractory Hairy Cell Leukemia

For information about the treatments listed below,

Treatment of relapsed or refractory hairy cell leukemia may include the following:

• Chemotherapy.
• Immunotherapy (interferon).
• Targeted therapy with a monoclonal antibody (rituximab).
• High-dose chemotherapy.
• A clinical trial of a new immunotherapy.
• A clinical trial of a new targeted therapy.
• A clinical trial of chemotherapy and targeted therapy with a monoclonal antibody (rituximab).

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done.

Complications

Hairy cell leukemia most commonly affects the bone marrow and spleen. However, because HCL travels between the bone marrow, spleen, liver, and lymph nodes via the bloodstream, it may potentially affect any part of the body that the blood circulates to. Therefore, other medical problems have been described that are likely a direct or indirect result of the hairy cell leukemia. This section will provide a brief review of both the common and uncommon complications of HCL.

When hairy cell leukemia is present in the bone marrow, it slowly increases over time until it begins to prevent normal blood cell production. This leads to lowering of the normal blood counts and may be manifested as low red cell counts (anemia), low platelet counts (thrombocytopenia), and/or lower than normal white blood cells (neutropenia, lymphocytopenia, and monocytopenia). Many of the symptoms and complications of HCL are a direct result of low blood cell counts.

In some patients, hairy cells will begin to circulate in the bloodstream and when this happens the white blood count may be higher than normal. Some patients with hairy cell leukemia have an elevated white blood cell count due to the presence of hairy cells in the bloodstream, but these are not normally functioning white blood cells and do not protect against infection. Whether the white blood count is high or low, patients with HCL are overall at increased risk of infection. In fact, infection is one of the leading causes of illness and death for patients with hairy cell leukemia. Infections can be caused by bacteria, viruses, or fungal diseases. In addition, some medications used to treat HCL can temporarily increase the risk of infection by decreasing the white blood cell numbers or normal functioning. For example, the chemotherapy agents most commonly used for the initial treatment of hairy cell leukemia – pentostatin and cladribine – can lower the number of normal lymphocytes. This side effect of therapy can last for many months and increase the patient’s risk of developing a viral disease (e.g., Herpes Zoster, commonly called shingles) or fungal disease that can cause pneumonia. Patients with HCL should not receive the older Herpes Zoster (shingles) vaccine (called Zostavax) from their physicians, as it is a live virus vaccine that might result in causing the very condition that it is intended to prevent. However, immunizations using killed virus vaccines, such as the influenza vaccine, are safe and may provide important protection for HCL patients. A newer, non-live shingles vaccine (called Shingrix) has more recently been introduced and patients with HCL should discuss this option with their doctors.

Lowering of the red blood cell count, or anemia, is often associated with symptoms of fatigue. Some patients with hairy cell leukemia will require a red blood cell transfusion to correct this problem, although this is a temporary solution until the HCL improves. Lowering of the platelet counts leads to an increased tendency to bleed, and many patients with low platelet counts notice an increased tendency to develop bruising or bleeding from the gums or nose. If bleeding is severe or the platelet count is very low, a platelet transfusion may be required. However, again this is a temporary solution until treatment is given to improve the underlying HCL.

In the past, significant enlargement of the spleen was a very common complication of hairy cell leukemia and was often the initial symptom of the disease. Although patients today are more often diagnosed with HCL on the basis of an abnormal blood count, many patients will still develop an enlarged spleen as part of the disease course. This may cause symptoms of abdominal pain, abdominal distention, or difficulty eating a full meal due to the pressure that the enlarged spleen exerts on the stomach. Most of the effective therapies for HCL will decrease the size of the spleen, relieving these discomforts.

It is possible to remove the spleen if need be, although this could lead to an increased risk of certain types of infection. Therefore, removing the spleen is usually only performed if other therapies are not possible or have not proven effective. When the spleen is very enlarged there is an increased risk of splenic rupture due to trauma, such as a car accident. Sudden pain in the abdomen followed by profound weakness should cause the patient to seek immediate medical care in an emergency facility.

There has been some concern that the therapy for hairy cell leukemia may increase the patient’s risk for developing a secondary cancer. This is an ongoing issue of debate. Some studies show that the disease itself may actually increase this risk. Therefore, people with HCL should continue to have their routine cancer screening performed at regular intervals based upon recommendations established by cancer experts.

References