Hairy Cell Leukemia is a rare disorder but one of the most successfully treated of all leukemias. Since the advent of new, effective, agents in the 1980s most patients will enjoy very prolonged disease remission (median of more than 15 years in one series) associated with normal quality of life and survival that is not significantly different from an age-matched population of individuals who do not have HCL. Although current treatment is not considered curative, different therapies can be given sequentially as needed to control the disease over many decades.

When to start treatment?

Not all patients will require treatment immediately after the diagnosis is made and can be monitored until it is needed. This ‘watch and wait’ surveillance approach can be difficult for patients and their families and generates a lot of anxiety. However, unlike other types of cancer, leukemias do not spread or metastasise and so waiting to start treatment until there are clear signs that it is indicated is perfectly safe and has the advantage of not exposing a patient to drugs, which may have side effects, earlier than is necessary. Other patients will clearly need treatment straight away because of symptoms and/or very low blood counts. The decision of when to start treatment depends upon the symptoms experienced by the patient and the degree of abnormality in the blood count. Often patients will remain entirely well even if they do need treatment because of a reduction in normal blood counts. This reduction is the usual reason for initiating treatment and it is preferable not to wait until the blood counts fall to very low levels even if the patient is well. Three types of cells may be reduced – red blood cells (causing anemia), white blood cells (which help fight infection) and platelets (which prevent abnormal bleeding and bruising). Not all may be low but most commonly the ability to fight infection is reduced and treatment is needed to restore this. After treatment there is almost always a further, temporary, fall in normal counts before they recover as it takes time for the disease to clear from the bone marrow. Recovery usually takes 3-6 weeks. Infection is the biggest risk, before, during and for a period after, treatment. It is important to treat any active infection effectively before any therapy for the HCL is started. It is rare that treatment is needed urgently for HCL. Therefore, careful clinical judgment is necessary to make the best decision for each individual patient regarding the optimal time to start treatment for the HCL.

What treatment to use?

For the past 30 years the mainstay of treatment for HCL has been with 2 drugs in the group of purine analogues called pentostatin and cladribine. Pentostatin was the first to be introduced in the 1980s and then cladribine in the early 1990s so there is now a great deal of experience and long-term follow up with these agents. Both are highly effective at inducing a remission (in almost 100% of patients) with no significant difference between the two. Most of these remissions are complete (CR) i.e. no sign of any remaining disease in the bone marrow using standard methods. Such remissions often last for very prolonged periods of time (more than 10 years).

How are these drugs administered and what are the side effects?

Pentostatin is administered as a short intravenous (IV) infusion every 2-3 weeks until a remission is achieved (usually 8-10 injections). It is excreted in the body by the kidneys and it is therefore important to check kidney function to ensure this is normal. The dose of pentostatin needs to be reduced if the creatinine clearance (measure of renal function) falls below a certain level. Patients can experience nausea up to 72 hours after the infusion and should have anti-sickness pills to take if needed.

Cladribine can be given in a number of ways including as a 7- day continuous IV infusion (which may require a hospital admission), daily or weekly IV infusions for 6 doses or as a subcutaneous injection on 5 consecutive days. There is no evidence that these are not all equivalent in terms of effectiveness and the choice will largely depend on the physician and patient. Most can be given as out patient treatment.
Both treatments are generally well tolerated but are associated with a temporary reduction in normal blood counts. This needs to be monitored closely until they recover (weekly initially). Sometimes the recovery of the blood counts can be delayed for a much longer time but eventually they do improve.

Pentostatin and cladribine also cause a more prolonged suppression of the immune system and advice should be given about the signs and symptoms of infection to be on the watch for. Infections should always be taken seriously as prompt treatment is important. Some doctors will also administer low doses of antibiotics/antivirals to reduce the risk of infections. In the case of cladribine it is better to start these after the 1-week course of treatment has been given since rashes can sometimes occur when the drugs are given concurrently. Occasionally growth factors (eg GCSF) may be given to speed the recovery of the white blood cells. Other supportive drugs such as allopurinol are not usually needed. Blood transfusions, if required, should be with irradiated blood.

Splenectomy is rarely undertaken now since other therapies are so effective in reducing the size of the spleen, which is often enlarged at the time of diagnosis.

Interferon is rarely used. It is not well tolerated and much less effective than the purine analogues, but occasionally may still be useful.

Rituximab used as a single agent in first line treatment of HCL is not as effective in inducing remissions as the purine analogues. Its use would be reserved for patients unable to tolerate purine analogues. There is early evidence that better remissions may be achieved with the combination of rituximab and a purine analogue (pentostatin or cladribine). Because of the very good results with purine analogues alone for most patients the addition of rituximab is often reserved for those patients who do not achieve a CR or who relapse earlier than expected after treatment.

Novel Agents: Targeted therapies such as immunoconjugates (moxetumumab pasudotox), BRAF inhibitors (eg vemurafenib) and B-cell receptor inhibitors (eg ibrutinib) all have activity in HCL. Currently these have been examined in relapsed or refractory HCL and only in a very small number of patients (in whom PAs cannot be given) as first line therapy. A number of clinical trials are being undertaken to evaluate these drugs further.

Clinical Trials: HCL is a rare disease and there are very few clinical studies being undertaken worldwide. It is important for patients to participate in clinical trials if at all possible, particularly if their disease has been hard to treat and they would particularly benefit from novel therapy.

Assessment of Response and Monitoring

Usually within a few weeks of receiving treatment the blood counts begin to recover and will often return to completely normal levels. However, to assess response an examination of the bone marrow is necessary. This will not be taken for at least 3-4 months as it takes time for the treatment to have its full effect. The BM is not pleasant for patients but does give important information about the quality of response to the treatment that has been given and whether or not more or different therapy may be needed. Studies have shown that in those patients who have obtained a CR, the remission lasts longer. There are other more sensitive laboratory methods which can assess ‘minimal residual disease’ or MRD, which may be present even in patients in a CR. It is not entirely clear what effect the presence of MRD has on outcome. MRD assessment is usually only undertaken in the setting of a clinical study and the results do not currently indicate any need to change the treatment plan. CT or US scans may be repeated, if they were abnormal before treatment, to assess response.
Around 40% of patients will relapse, even if this is after 10 years or more. Regular monitoring by a hematologist will usually take place. This may only be once or twice a year for patients in a stable remission. Relapse is usually indicated by falling blood counts and confirmed by examination of the bone marrow. Retreatment is nearly always successful although the remissions tend to last for a shorter period of time when the same treatment is given again.