About Hairy Cell Leukemia

Michael Grever, MD

The Ohio State University

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What is Hairy Cell Leukemia?

Hairy cell leukemia is a chronic and relatively rare form of adult leukemia. It is estimated that approximately 2 % of all adult patients with leukemia have this form of disease. While the cause of this malignancy is not known, the origin of the malignant cell is thought to develop from the memory B cell compartment. These malignant cells infiltrate the bone marrow, the spleen, and the liver from the time of diagnosis. In the spleen, there is a characteristic location of these leukemic cells in the splenic red pulp. While lymph nodes in the abdomen may be involved, lymph nodes are rarely enlarged on physical examination. The original description of this malignancy included a number of patient cases that were reported in 1958.

For many years, the origin of this malignant cell was debated. It is now generally held that this is a malignant B cell that is found predominantly in the bone marrow and spleen. These cells do circulate in the blood as well.

This disease usually is gradual in onset. Patients present with fatigue, increased susceptibility to infection, and enlargement of the spleen. The malignant cells in the bone marrow compromise the usual production of normal red cells, white blood cells, and platelets that are manufactured in the bone marrow.

There are approximately 500 new cases of this disease discovered every year in the United States. There is an unexplained larger number of men than women afflicted with this leukemia. This disease is treatable, but not curable. While the cause is not known, the treatment is usually very effective in helping patients lead a normal life.

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History of HCL

In 1958, Dr. Bertha Bouroncle and colleagues described 26 patients with this disease that she called “leukemic reticuloendotheliosis.” In this original description of a large series of patients, she identified the clinical presentation and features of this disease. Thus, this entity was recognized as a separate form of leukemia and was characterized by monotonous cells with a serrated border. The leukemic cells were present in the peripheral blood and had projections emanating from the cytoplasmic border. Ultimately, this disease was called “hairy cell leukemia.”

While unexplained, this disease has a male predominance with a ratio of 4:1 men to women with a median age at diagnosis of 52 years. There is a wide range of ages for patients with this disease. The main presenting symptoms include fatigue or weakness. Infection may also be quite prominent as a result of neutropenia and monocytopenia. Patients may present with bacterial or opportunistic infections. Patients may complain of early satiety as a result of an enlarged spleen. Finally, there are an increasing number of patients who are without symptoms, and present for diagnosis because of an abnormal screening blood count or physical examination. Consequently, it is typical for patients to be referred for evaluation of some combination of anemia, neutropenia, thrombocytopenia, and splenomegaly.

Before 1984, the treatment of this disease was unsatisfactory. Available chemotherapy included alkylating agents that often caused worsening of blood counts. In general, patients were often referred for splenectomy that temporarily improved the low blood counts. While other therapy was also attempted, the median survival was approximately 4 to 4.5 years in patients who were treated with removal of the spleen. Responses to alpha-interferon were first published by MD Anderson Hospital in 1984. Subsequently, other investigators confirmed the benefit of interferon. Marked improvement in blood counts meeting the definition of response were observed in about 80% of patients with 10% achieving complete remissions. In the same year 1984, a report by Spiers and colleagues indicated that complete remissions were also observed in a small cohort of patients with hairy cell leukemia who were treated with Pentostatin.

Subsequently, Pentostatin was reported by other groups to secure a complete remission in 75 to 90% of patients who were previously untreated. In 1990, the first report of Cladribine administered by a seven-day intravenous infusion showed a complete remission in 11 out of 12 patients. While patients with an active infection were not included in these trials, the extraordinary high complete remission rate following a single course of therapy was reproduced in a large series of patients by the investigators at Scripps Clinic. Other investigators using alternative schedules of Cladribine found complete remissions in 76 to 81% of patients.

Long-term follow-up studies on patients treated with either Pentostatin or Cladribine have shown that about 60% of patients remain in remission at 10 years of follow-up. In the approximate 40% of patients who relapse, there is a high chance of achieving a second remission. Second complete remissions with both purine agents have been reported to achieve complete remissions ranging from 52 to 75% of patients.. As a result of these remarkable results, the natural history of patients with this disease has been substantially improved with the use of these purine agents. Patients with hairy cell leukemia have a near normal life expectancy compared to the much poorer results of three decades ago.


Symptoms

Many patients do not have symptoms, but are found to have an abnormal blood test or an enlarged spleen on physical examination.

The most common symptoms relate to fatigue, increased number of infections, bleeding or bruising.

Some patients experience symptoms from an enlarged spleen with fullness in the abdomen. This can also cause a sensation of being very full after meals. Rarely, patients with hairy cell leukemia develop a condition called “vasculitis” that is associated with variable symptoms (e.g., skin rash and fever). Patients have also had some involvement of their bones with this disease.


How is the diagnosis of Hairy Cell Leukemia established?

In patients who are having symptoms from this disease, there is often an enlarged spleen felt on physical examination. In the original series published by Dr. Bouroncle, more than 90% had an enlarged spleen. Subsequently over the years, the finding on an enlarged spleen is more often identified in about 80% of the patients. Therefore, the failure to identify an enlarged spleen does not preclude the diagnosis of hairy cell leukemia. Most patients will have reduced hemoglobin, neutrophiles, and monocytes. Thrombocytopenia is also quite common. A careful examination of the peripheral blood smear will identify the circulating leukemic cells with a serrated cytoplasmic border.

If the physician is planning to find the cause of an enlarged spleen or the reason for an abnormal blood test, you will need to have a physical examination and blood work drawn.

The spleen is located in the upper left side of your abdomen. Sometimes the spleen is enlarged and can be felt by the physician during your examination. It may be necessary for the physician to order a CAT scan of the abdomen to look for the size of the spleen. This study may also show enlargement of lymph nodes that are located in the abdomen.

Your blood work will often show anemia (low red blood cell count), low white blood cell count with abnormal forms of cells, and a low platelet count (that can predispose to bleeding). On reviewing the blood smear, the appearance of cells with hairy borders can be observed. These leukemic cells have a distinct appearance under the microscope. You may also have a reduced number of the normal white blood cells that protect from infection. The absolute numbers of these cells can be useful in determining when treatment should be initiated as well as in establishing the diagnosis.

There are sophisticated studies that can be done on your blood sample to identify certain markers on the surface of the leukemic cells. The markers are called immunophenotype markers. There are characteristic patterns of markers expression that will help to confirm the correct diagnosis.

The physician will likely refer you to a hematologist or oncologist who specializes in the diagnosis and treatment of patients with leukemia. Patients often have a bone marrow biopsy performed that will help in understanding the diagnosis and treatment options. A bone marrow biopsy is performed by using a needle to take a sample of bone from the area near the rear area of your hip. While this is painful, the physician can give both local and other medication to reduce the pain. This procedure is relatively quick, and provides a very useful confirmation of the diagnosis.


Complications

One of the leading causes of death for patients with hairy cell leukemia is infection. Prompt attention to fever and symptoms related to infection are important.

Infections can be caused by bacterial, viruses, fungal disease. The increased risk of infection is the result of impaired bone marrow production of infection fighting cells. The treatment of the disease can temporarily increase the risk of this complication. The chemotherapy used to successfully treat this leukemia can temporarily make the infection fighting cell counts lower, and therefore increase the risk until recovery from treatment occurs.

In addition to bacterial diseases, the treatment for this disease can lower the number of normal lymphocytes in the patient. This side effect of therapy can last for many months, and increase the risk from viral disease (e.g., herpes zoster or shingles) or fungal diseases that can cause pneumonia. It is important to be aware of the risk for infection and to avoid contact with others who have an infection. Patients with hairy cell leukemia should NOT receive the herpes zoster vaccine from their physicians, as this is a live virus vaccine and might result in causing the condition that it is intended to prevent.

There has been some concern that the therapy for hairy cell leukemia may increase the patient’s risk for developing another secondary cancer. This is an ongoing issue of debate. Some studies show that the disease itself may increase this risk. Therefore, patients need to have their regular check-up to maintain a healthy life, and follow the recommendations of their physicians in routine screening for cancer based upon recommendations established by cancer experts.

Patients with hairy cell leukemia have on rare occasions developed a ruptured spleen. While this may occur after a blow to the abdomen, there have been rare cases reported of a spontaneous rupture. This complication requires immediate medical attention, and may require surgical removal of the spleen. Sudden pain in the abdomen followed by profound weakness should result in seeking immediate medical care in an emergency facility.

Bleeding can be a complication of a lowered platelet count. This may result from bone marrow involvement with leukemia, an enlarged spleen, or from therapy for the disease. If the platelet count is dangerously low, the physician should warn the patient of signs and symptoms of this complication. While splenectomy used to be a frequent therapy for this disease, it is not often used because the chemotherapy is effective in shrinking enlarged spleens. In the case of active bleeding and an enlarged spleen, there may be an indication for splenectomy to improve the dangerously low platelet count. The improvement in platelet count with chemotherapy requires several weeks, and this may not be quick enough if bleeding is a serious threat to the patient. Because the surgical removal of the spleen involves a long-term risk for patients by increasing susceptibility to infection, the decision to do this surgical procedure needs to be carefully considered.


>Treatment

Rather than receiving immediate therapy for hairy cell leukemia, some patients are told that they should undergo a “watch and wait” surveillance approach. This idea of not immediately treating leukemia can elicit anxiety on the part of the patient, their family and friends.

This disease cannot be cured with current therapy, but it can be effectively treated in the majority of patients. Treatment results in prolonged control of the disease, but starting treatment before there is a clear indication does not directly benefit the patient. In fact, treatment started too early may cause harm for a patient who has no symptoms.

The decision of when to start treatment depends upon the symptoms experienced by the patient. In patients without symptoms, there is less reason to take the risks associated with treatment. The drugs that are used to treat this disease are very effective, but they can actually lower the blood counts before there is improvement. There is no proof that starting therapy before the blood counts are starting to decline will change the long-term outcome. It is clear that if the blood counts drop to dangerously low levels, then the risks of treatment and the outcome are worse. Therefore, careful clinical judgment is necessary to make the best decision for the patient.

In general, if the patient is developing anemia, or severe depression of the “infection-fighting” white blood cells, or platelets (that prevent bleeding), treatment should be started. It is important to also consider the health of the patient before starting therapy. Some patients with an active infection have been excluded from trials with Cladribine. So, if a patient has an active ongoing infection, it will be important to appropriately treat the infection. A decision will be necessary on which therapy would be best to use to treat the hairy cell leukemia under this circumstance. Some individuals have recommended that patients with hairy cell leukemia who have an active infection could receive Pentostatin or interferon as initial therapy. Others have recommended getting the infection under control, and then treating the leukemia. It may, however, be necessary to treat the leukemia while aggressively treating the infection.

In treating the patient with this disease, there are several highly effective agents. Patients should also have their kidney function evaluated before starting therapy, as both agents that are most frequently used Cladribine and Pentostatin are excreted through the kidneys. In particular, the dose of Pentostatin may need to be reduced if there is abnormal kidney function. In general, the overall health of patients with this disease should be carefully evaluated before starting therapy.

The two agents that are most frequently used as initial therapy are either Cladribine or Pentostatin. Both agents are capable of inducing a complete remission in a very high percentage of patients. There are several different ways of administering these drugs for patients with this disease. The largest experience in the United States with Cladribine involved a seven day intravenous administration of the drug as described by Scripps Clinic. Other investigators both within the United States and in Europe use different ways of giving this drug. Some physicians give a dose of Cladribine each day over five days for several hours. Others have given this drug once a week for six doses. A few investigators have suggested that the drug can be given by an injection under the skin. So, there are several different ways of giving this drug, and your physician will be able to explain how it will be given to you.

If Pentostatin is given, it is usually administered as a short intravenous injection once every two weeks. In some patients, there has been an intentional delay of a week between doses at the beginning of therapy, so that the drug is given every three weeks. This delay is intentionally selected if the blood counts are very low or go low after the first dose. It usually takes several weeks for the blood counts to start to improve after these drugs are given. Some judgment about dosing is necessary based upon the patient’s response, but in general this drug can be given in full dose on schedule once the blood counts have started to improve. Patients receiving Pentostatin usually are treated in the outpatient clinic every other week for months to achieve a complete response. Once the blood counts start to improve and the spleen returns to normal size, the patient begins to feel better. This outpatient method is usually well-tolerated, but may take several months to complete a course of therapy. In contrast, treatment with Cladribine is usually completed in either one week or six weeks depending upon how the drug is administered.

When either drug is being used, there is a tendency for the blood counts to go lower before they improve. Therefore, patients need to be monitored closely for fever and signs of infection. Therapy for infection needs to be initiated promptly in these patients. Blood counts should be followed very closely until the numbers have reached safe levels as determined by the treating physician. The overall outcome of each of these two drugs is basically the same. Long-term studies are now available that show approximately 40% of patients will eventually relapse, and may require re-treatment.

What is the rationale for “watch and wait” rather than embarking directly on treatment?

The purine agents that are used to treat hairy cell leukemia have clearly been highly effective in achieving a complete remission. However, the disease is not cured by the achievement of a complete remission using standard single agent therapy. We understand that there is substantial remaining disease called “minimal residual disease” that can be observed by using histochemical stains after observing a complete remission by the usual light microscope. There is no evidence that early intervention in an asymptomatic patient with marginal reduction in peripheral blood counts improves survival. Because the single agent therapy is not curative, it is difficult to recommend therapy in a truly asymptomatic patient. Furthermore, we know that the purine analogs can induce prolonged immunosuppression. Their use in a non-protocol setting for a stable patient with decent counts must be weighed against the potential side-effects.


Removal of the Splleen

The majority of patients with hairy cell leukemia will have enlargement of the spleen. In the past, removing the spleen (splenectomy) was the only method for offering treatment to these patients.

Removal of the spleen frequently results in an improvement of the blood counts, but there are consequences. Patients who have had a removal of the spleen remain at high risk for overwhelming serious bacterial infections for life. Some patients are protected by giving specific vaccinations to help prevent the long-term consequences of removing this organ. However, the drugs that are now available to treat this disease have made splenectomy less important in the management of this disease. Most patients will have shrinkage of the spleen with these drugs.

In patients who have active bleeding associated with a dangerously low platelet count, splenectomy may be life-saving. The improvement in the platelet count usually takes weeks to happen after the use of chemotherapy. If the patient is actually at risk of life-threatening bleeding, splenectomy may markedly improve the platelet count and reduce this risk.


Resistant Disease<

In those patients who fail to respond to either drug (Cladribine or Pentostatin), it is important to establish that the correct diagnosis was made.

Patients with the atypical variant of this disease do not respond as well to these standard agents. If the patient is non-responsive, splenectomy may be required. Alternatively, the patient could be referred to the National Institutes of Health (Dr. Kreitman at the National Cancer Institute) for experimental therapy. Some patients who failed on these other alternatives have responded to immune toxin conjugates.

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Clinical Follow-upp and Relapse

Patients who are treated should have a bone marrow biopsy performed following treatment to determine if a complete response has been achieved. In patients who have achieved a complete response by viewing the bone marrow under the microscope, it is not unusual to find minimal residual leukemia if more intense studies are done.

This may be one reason that some patients ultimately relapse. The question as to the need for additional therapy to eradicate minimal residual disease is a topic under current investigation.

Patients are usually followed quarterly after they have completed therapy. Routine blood counts are obtained to insure that the remission is being maintained. If blood counts show a decline, a repeat bone marrow may be obtained to see if the disease is relapsing. Alternatively, blood work can be drawn to search for evidence of recurring leukemia. Flow studies can be performed to identify small populations of leukemic cells. In addition, there are laboratory studies that can measure soluble factors or chemicals in the blood that may herald a relapse.

If relapse has been documented, careful consideration is given to decide when to re-initiate treatment. Just as there is a watchful waiting approach at the time of initial diagnosis, a similar strategy may be followed in patients who are totally without symptoms. A small decline in the blood counts may not be sufficient to warrant re-treatment. However, there is an advantage to re-starting therapy before the counts deteriorate to very low dangerous levels.


Use of Other Agentts

In addition to the use of drugs (Cladribine or Pentostatin), some patients are treated with a monoclonal antibody called Rituximab.

This antibody is able to attach to the leukemic cells in this disease. Hairy cells express a marker called CD20. Rituximab is an antibody that attaches to CD20 and can result in the death of the leukemic cells. This agent has been useful in treating some patients with non-responding hairy cell leukemia. In addition, there are studies that have used this agent to treat patients with minimal residual leukemia. The use of this agent for eradicating minimal residual disease is still an ongoing research approach.

Interferon is an agent that produced responses in about 80% of patients with hairy cell leukemia. The number of patients achieving a complete response is much lower (e.g., 10%). While the effectiveness of this agent is far lower than that with the usual drugs used to treat these patients, this agent can still help to improve blood counts in patients who are unable to tolerate the standard drugs.


Long-Term Outcome & Living with Hairy Cell Leukemiah2>

In those patients who fail to respond to either drug (Cladribine or Pentostatin), it is important to establish that the correct diagnosis was made.

Patients with the atypical variant of this disease do not respond as well to these standard agents. If the patient is non-responsive, splenectomy may be required. Alternatively, the patient could be referred to the National Institutes of Health (Dr. Kreitman at the National Cancer Institute) for experimental therapy. Some patients who failed on these other alternatives have responded to immune toxin conjugates.

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Living with HCL

How will this disease impact my life?

How this disease impacts your life depends on the following:

  • Whether the disease grows so slowly such that no treatment is
    needed;
  • The number of healthy blood cells in the blood and bone marrow;
  • Whether there are symptoms of the disease, such as recurring
    infections;
  • Whether the spleen is so enlarged that it causes symptoms.

If treatment is needed, the impact of HCL on your life depends on:

  • Whether the hairy cell leukemia responds to primary treatment;
  • Whether the leukemia has come back after previous treatment.

The treatment phase for hairy cell leukemia is usually of short duration, ranging from just 5 to 7 daily IV administration of Cladribine for one cycle, or initial bi-weekly, then monthly IV administrations of Pentostatin for a total of some 4 months. Treatment usually results in a long-lasting remission in most (95%) of the patients. If the leukemia returns after it has been in remission, re-treatment often induces another remission.

A majority of patients can expect a disease-free time span of about ten years, or sometimes much longer after initial treatment. 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.

Most of the patients are relieved to have the challenges of treatment behind them. No matter whether the initial treatment schedule is for 5 to 7 days or consists of weekly to monthly injections for 3 - 4 months, the maximum effect of chemotherapy will be achieved 3 to 4 months after the beginning of chemotherapy. Thereafter you will probably feel well and can expect life to return to “normal”, i.e. to the way before the diagnosis of HCL was made. For some patients, recovery might take much longer. Some patients may not feel “normal” or may not be able to do things they once easily did.

How soon after treatment you can feel "normal" again depends on several factors, including:

  • How advanced the HCL was at the time of treatment;
  • Your health conditions other than HCL;
  • Whether you have achieved a "complete remission" or a partial
    remission after treatment;
  • Whether you have experienced any of the rare, but serious side
    effects such as severe neutropenia, fever and infection, or
    kidney failure during or after treatment;
  • Whether you have experienced unusual distress and psychological
    trauma from the diagnosis.

Given the present success rates of treatment, the life expectancy for patients with HCL is close to that of the general population. In all patients, the first two years after diagnosis have the highest risk for serious or fatal complications. Surviving the first five years probably portends good control of the disease. It seems that after five years' clinical remission, patients with normal blood counts might have a normal life expectancy.

Many patients report that life after HCL treatment has new meaning. Some have mentioned that the experience of treatment has led them to make important changes. Changes might include the way you eat, the things you do, and your sources of support. Many have reported they have learned how to take better care of themselves and have become more health conscious. Others have benefited from joining support groups and have become actively involved in promoting research in treatment of HCL.

The impact of the disease for patients with the variant form of the disease (HCL-V) is not so easy to answer. This form is extremely seldom and survival is also complicated by the relatively high median age (70 years old) at diagnosis. It seems that HCL-V patients might survive for more than 10 years.

How often will I need to see the doctor after my treatment is completed?

After successful treatment, you should return to see the doctor for regular medical checkups for two reasons:

  • Despite high rates and long durations of remission, the disease
    is considered incurable. Relapses might occur even after more
    /> than twenty years of continuous remission. Patients will require lifelong monitoring. The disease can return even after decades
    of good health.
  • HCL patients might have twice the risk of developing another
    cancer, with a peak of about two years after diagnosis of HCL.
    Thereafter the risk falls steadily. There is also a higher risk
    of developing an autoimmune disease, which may also be brought
    under control upon successful treatment of HCL.

In general, patients with HCL usually return to the doctor every 3 to 4 months during the first 2 years after treatment, and once or twice a year after that. Most specialists recommend a yearly visit to the doctor for the rest of the patient's life, and getting blood counts twice a year.

At these visits, your doctor will look for side effects from treatment, and check for signs of recurrence.

At these visits, your doctor will:

  • Review your medical history since the last visit
  • Give you a physical exam

Your doctor may run follow-up tests such as:

  • Complete blood counts
  • Lab work such as soluble CD25
  • MRI or CT scans.

Many patients keep their medical records in a folder and refer to them as they see new doctors. It might be useful to keep your own records on:

  • The date you were diagnosed with HCL;
  • Pathology report of the bone marrow or other biopsy material;
  • Place and dates of specific treatment;
  • Names and doses of chemotherapy;
  • Key lab reports, x-ray reports, CT scans, and MRI reports;
  • List of possible short-term and long-term side effects of the
    specific treatment that you have received;
  • Contact information for all health professionals involved in
    your treatment;
  • Any problems that occurred during or after treatment;

For follow-up care, the doctor may be the same who provided your treatment. Depending on where you live, it may make more sense to get follow-up care from your family doctor.

Between regularly scheduled appointments, patients with HCL should report any health problems, especially viral or bacterial infections, and see their attending physician as soon as these problems occur.

Will I be able to return to work?

Treatment of HCL often results in a long-lasting remission. Most patients (>90%) are able to return to work upon successful treatment. Patients usually feel fit enough to return to work once they have achieved normal blood counts, which may happen 2 to 3 months after beginning of chemotherapy.

How soon you can return to work depends on several factors:

  • How advanced the HCL was at the time of treatment;
  • Your health conditions other than HCL;
  • Whether you have experienced any of the rare, but serious side
    effects of chemotherapy such as severe neutropenia, fever,
    > infections, or kidney failure.

Many patients have tolerated the treatment so well that they have continued to work during the whole treatment phase, which for hairy cell leukemia is usually of short duration.

Some patients with advanced disease and poor blood counts might not feel well enough to return to work in the first 3 months, or might suffer from infectious complications during the treatment phase. Others might need even longer. The highest risk for serious or fatal complications was observed in the first two years after diagnosis.

Many patients with HCL report that staying active and performing moderate exercise during and after treatment can help them to return to work earlier. Moderate exercise (walking, biking, swimming) for about 30 minutes every day can reduce anxiety, improve self-esteem, and reduce fatigue or nausea. Patients with severe cytopenia (too few healthy blood cells) may need to take special care in exercising. Consult your doctor before you begin any exercise program.

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HCL and osteoarthritis

When I was first diagnosed 13 years ago, my doctor explained that the HCL cells were infiltrating my spleen and possibly my liver, blocking blood vessels all over my body and causing severe trombocytopenia. That explained the hemorrhages, chronic fatigue, muscle weakness, acute abdominal pains, and peripheral circulatory problems. After a first course with Cladribine I remained HCL-free for 3 years. Then I was diagnosed as a relapsed patient and had a second course of the med. Three years ago I started feeling lethargic and weak and developed osteoarthritis. Since my doctor had told me my blood counts would never go back to normal (they haven't), due to scarified tissue in my bones that would impair normal bone marrow levels in my body, I wonder if there is any connection between these two conditions. Could the HCL have made my bones more susceptible to arthritis?

Please submit your questions

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Please submit your questions through the HCL Mailbag so that the experts get a copy and can answer as promptly as possible. You can find the HCL Mailbag at http://www.hairycell.org/mailbag<.