When to Start Treatment and Which Treatment to Use for Hairy Cell Leukemia

Hairy Cell Leukemia (HCL) is a rare malignancy, but one of the most successfully treated of all leukemias. Since the advent of effective agents in the 1980s, most patients will enjoy very prolonged disease remission. Although current treatment is not considered curative, different therapies can be given sequentially as needed to control the disease.

Careful and experienced clinical judgment is necessary to make the most appropriate decision for each individual patient regarding the optimal time to start treatment as well as which agent to select to treat the patient’s HCL.

When to start treatment?

The decision of when to start treatment depends upon the character of the symptoms experienced by the patient and the degree of abnormality in the blood count.

Not all patients will require treatment immediately after the diagnosis is made and can be monitored until it is needed. This is termed “active monitoring” and helps avoid the potential side effects of treatment when not necessary. This watch and wait approach can be difficult and anxiety-provoking for patients and their families. However, unlike other types of cancer or some other more acute subtypes of leukemias, it is safe to wait to start treatment for hairy cell leukemia until there are more definite signs that treatment is really needed.

Many patients will clearly need treatment at the time of diagnosis because they have symptoms which may be disease-related and/or very low blood counts. A reduction in blood counts is the usual reason for initiating treatment and it is safest not to wait until the blood counts fall to very low levels, even if the patient feels relatively well.

Three types of cells may be reduced – red blood cells (low red blood cell counts cause anemia and symptoms like tiredness and loss of energy), white blood cells (which are needed to help fight infection), and platelets (which prevent abnormal bleeding and bruising). Not all of the above cell types may be low at the same time. However, patients with HCL most commonly have a reduced ability to fight infection and so treatment of the hairy cells is needed to help restore this capability.

The major drugs used to treat HCL can temporarily lower the blood counts before they eventually improve, so careful attention and efforts to control active infection are needed. It is important to always treat any active infection effectively before starting initial or continuing therapy for the HCL itself.

After treatment there is almost always a further, temporary fall in normal blood counts before they eventually recover. This is because it takes time for the disease to clear from the bone marrow. Recovery usually takes 3-6 weeks, but it depends on the treatment and the patient’s response.

 What treatment to use?

For the past 30 years, the mainstay of treatment for HCL has been pentostatin and cladribine, two  drugs in the class called purine analogues. Pentostatin was introduced in the 1980s followed by cladribine in the early 1990s. Today, there is a great deal of experience and long-term follow up  using these two agents. Both are highly effective in inducing clinical response and a remission (in almost all patients), with no significant difference in efficacy between the two. Most of these remissions are complete (i.e., no evidence of any remaining disease in the bone marrow using standard methods). Such remissions often last for  prolonged periods of time, sometimes even more than 10 years.

In September 2018, moxetumomab pasudotox, an anti-CD22 immunotoxin, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with HCL who have already received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Approval was based on a clinical study of 80 patients with HCL or HCL variant: 77 with classic HCL and 3 with HCL variant. Of these patients, 41% achieved complete remission (CR). Most CRs were without minimal residual disease, which if still present may eventually result in relapse. The approval of moxetumomab pasudotox by the FDA represents an exciting new treatment for patients whose leukemia develop resistance to standard treatments.

How are drugs used to treat hairy cell leukemia currently administered? What are the usual side effects?

Pentostatin is administered as a short intravenous (IV) infusion every 2-3 weeks until a remission is achieved. Pentostatin is excreted from the body by the kidneys and thus it is important to check kidney function to ensure that it is normal before giving the drug. Patients can experience nausea up to 72 hours after the infusion and they should have anti-nausea medication available in case they need it.

Cladribine can be given in a number of ways, including as a 7- day continuous IV infusion (which may require  hospital admission), daily IV infusion over 2 hours for 5 doses or weekly for 6 doses, or as a subcutaneous injection on 5 consecutive days. All modes of administration have been shown to be effective. The choice will largely depend on the physician and patient and most are given as outpatient treatment.

Both drugs are generally well tolerated but are associated with a temporary reduction in normal blood counts, which need to be monitored closely (weekly initially) until recovery. Sometimes recovery of the reduced blood counts is delayed for a much longer time, but eventually they improve.

Pentostatin and cladribine may also cause a more prolonged suppression of the immune system, and patients should be informed of this possibility and be made aware of signs and symptoms of possible infection. Infections should always be taken seriously as prompt treatment is important. Some doctors will also administer low doses of antibiotic/antiviral agents in order to reduce the risk of infection. In the case of cladribine, it is better to start these agents after the 1-week course of treatment has been given, since rashes can sometimes occur when the drugs are given concurrently. Blood transfusions, if ever required, should be with irradiated blood.

Splenectomy is rarely performed nowadays since the agents used today are very effective in reducing the size of the spleen. The spleen is often enlarged at the time of diagnosis.

Interferon was used in the past, but is rarely used today. It is not well tolerated and much less effective than the purine analogues, but occasionally may still be useful if patients fail initial therapy.

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 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 HCL patients who do not achieve a complete remission or who relapse earlier than expected.

Targeted therapies such as BRAF inhibitors (vemurafenib) and B-cell receptor inhibitors (ibrutinib) have activity in HCL. Currently, these therapies have been examined in relapsed or refractory HCL and only in a very small number of patients for whom purine analogues cannot be given as first line therapy. A number of clinical trials are ongoing to evaluate these drugs further in hopes of sparing the immunosuppressive effects of purine analogues.

Moxetumumab pasudotox (Lumoxiti) is administered as an intravenous infusion over 30 minutes on days 1, 3, and 5 of each 28-day cycle. Lumoxiti may cause serious side effects, including capillary leak syndrome and hemolytic uremic syndrome.

HCL is a rare disease and there are very few clinical studies being undertaken worldwide. To continue to make progress in new therapies, it is important for patients at every stage of treatment to consider participation in clinical trials. We encourage patients to visit our clinical trials page to learn about trials underway that may be right for them.

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 to anti-HCL treatment, a bone marrow examination is necessary. This is usually done 3-4 months after cladribine therapy to assess the full impact of therapy. The bone marrow procedure is not pleasant for patients, but does provide important information about the quality of response to the treatment  given and whether or not more or different therapy is needed. Studies have shown that in those patients who have obtained a clinical complete remission, the response lasts longer. There are other more sensitive laboratory methods which can assess for any measurable minimal residual disease (MRD). MRD may be present even if patients are in complete remission. It remains to be determined what effect the presence of MRD has on outcome and this is an area of ongoing research.

About 40% of patients will relapse, even 10 years or more after initial therapy. Regular monitoring by a hematologist takes place, usually once or twice a year for patients in stable remission. Relapse is usually suspected in patients who have falling blood counts and should be confirmed by examination of the bone marrow. Re-treatment is often successful although the subsequent remissions tend to last for a shorter period of time, when the same therapeutic agents are given again.