Hairy Cell Leukemia Treatment & Management

Management decisions

In hairy cell leukemia (HCL) patients, the absence of declining peripheral blood cell counts may be used to select patients who can be observed closely on a watch-and-wait program. ^[15] The careful follow-up of the patient who is being observed entails at least quarterly blood cell counts and physical examination. If the patient develops a sustained decline in the blood cell counts or becomes symptomatic with generalized symptoms of fatigue or splenomegaly, then therapy is started before the counts decline to dangerously low levels. The initiation of either cladribine or pentostatin may be associated with a temporary worsening of the blood cell counts, so intervention should definitely begin before these hematologic parameters have deteriorated to the levels requiring support. Because either of these agents is highly effective as monotherapy, most clinicians select the agent, dose, and schedule that they have effectively used in the past.

The data using either pentostatin or cladribine alone for hairy cell leukemia suggest that these agents are equally effective in terms of response rate and remission duration. ^[16] Furthermore, the long-term adverse effects are quite comparable. The concerns regarding increased risk for either late infections or secondary malignancies have not been fully resolved.

Patients have had a substantial improvement in overall survival as a result of the initial use of either analog. Although they need to be closely observed for late adverse effects of therapy, patients with hairy cell leukemia may now live as long as they would have without this diagnosis. The progress in treatment changed the natural history of this disease. Although there is still not a recognized best way to initiate therapy, there is a consensus that attaining a complete remission is important because of the possibility of a late relapse. In selecting appropriate chemotherapy, several clinical features must be considered.

Other issues in management decisions

Is there evidence of active, untreated, ongoing infection?

Although it is prudent to attempt to effectively treat an active infection before administering a purine nucleoside analog to a patient with hairy cell leukemia, the profound neutropenia and monocytopenia related to the disease may force the decision to start effective therapy. Otherwise, the patient may succumb to the infection. However, purine analogs may temporarily worsen the hematologic parameters. Most of the initial reports of cladribine indicate that this agent should not be administered to a patient with an ongoing infection. ^{[17, 18]}

One strategy involves treating the patient with interferon alfa to obtain an improvement in the granulocyte count that may enable the antibiotic or antifungal therapy to be more effective in controlling the infection, followed by a definitive purine analog therapy to achieve complete remission. ^[19] The complete remission rates of interferon in uninfected versus infected hairy cell leukemia patients were low, at 11% verus 5%, respectively.

Alternatively, use pentostatin because of data used in hairy cell leukemia patients with infections were included, and, although complete remssion rates in the uninfected group was better (78% vs 68%, respectively) and the frequency of febrile episodes requiring antibiotic therapy was 27% after, the recommendation is to control the infection if possible before starting pentostatin.

The use of G-CSF on cladribine-induced neutropenic fever in hairy cell leukemia patients show that it can raise absolute neutrophil count and shorten the period of neutropenia, but not in uninfected patients. ^[20]

Does the patient have a good performance status and adequate renal function?

Pentostatin is cleared through by the kidneys, thus renal function must be carefully monitored during therapy. Patients with serum creatinine of 1.5 mg/dL or higher should be excluded from receiving the drug and the initial dose is reduced to 2 mg/m² if the performance status was impaired, with subsequent escalation to full-dose therapy if tolerated. Patients on therapy are usually hydrated with 1.5 L of fluids along with each dose of the drug and serum creatinine is checked before each new infusion.

Chemotherapeutic approaches

The first-line therapy for hairy cell leukemia is 2-chlorodeoxyadenosine (2-CdA) 0.1 mg/kg/d (Cladribine, Leustatin) by continuous intravenous infusion for 7 days, which can be performed on an outpatient basis with a pump, using a percutaneous intravenous central catheter (PICC). ^{[21, 22, 23]} Growth factors are not routinely given but may be added in patients with febrile neutropenia. The response is usually first observed in the platelet counts (in 2-4 wk) followed by white blood cell counts and neutrophils and, finally, hemoglobin levels. Bone marrow biopsy is repeated in 3 months, but minimal residual disease does not need therapy.

With one course of therapy of 2-CdA, 80% of patients obtain a complete remission (CR), and the remainder obtains a partial remission (PR). Several long-term studies have been reported. Chadha et al reported that, although the overall survival rate at 12 years was 87%, the progression-free survival at 12 years was only 54%. ^[24] In addition, 17% of patients had developed another malignancy during that time.

For increased convenience, some groups have given 2-CdA as a 2-hour infusion (0.14 mg/kg/d) for 5 days. Zinzani et al reported a CR rate of 81% and a PR rate of 19% using this schedule. ^[4] The 13-year overall survival rate was 96%, and the relapse-free survival rate was 52%. ^[4] No randomized study comparing the 24-hour infusional versus the 2-hour infusional schedules is available.

A current trend is the significance of minimal residual disease following treatment with 2-CdA. Ravandi et al administered rituximab to patients with residual disease following 2-CdA. ^[25] Eleven of 12 patients had eradication of minimal residual disease with this treatment. Whether this will alter the natural history of hairy cell leukemia or prevent relapse is unclear. Currently, the standard therapy for patients with minimal residual disease is observation.

For patients with relapsed hairy cell leukemia who have previously been treated with splenectomy, interferon, or 2-deoxyformycin (2'-DCF, Pentostatin), retreatment with 2-CdA in the same manner is indicated, especially if their disease had previously responded to 2-CdA. In patients previously treated with 2-CdA, response rates of 50% are typical. ^[26]

Rituximab is a monoclonal antibody against CD20. In patients with relapsed or refractory hairy cell leukemia, response rates of 50% are reported.

Hairy cell leukemia may behave as a chronic leukemia without causing any symptoms. Approximately 10% of cases, usually in elderly men with moderate splenomegaly and mild decrease in blood counts, never require therapy.

The standard criteria for initiating therapy include the following:

• Symptoms or blood transfusion requirement
• Significant anemia with hemoglobin of 8-10 g/dL or less
• Thrombocytopenia with platelet counts of 50,000-100,000/mL or less
• Neutropenia with an absolute neutrophil count (ANC) of 500-1000/mL or less (see the Absolute Neutrophil Count calculator)

Less common indications for therapy include the following:

• Leukocytosis with a high proportion of hairy cells
• Repeated life-threatening infections
• Symptomatic splenomegaly
• Bulky or painful lymphadenopathy
• Vasculitis
• Bony involvement

For patients with hairy cell leukemia that is refractory to 2-CdA, or if relapse occurs after 2 cycles of 2-CdA, the authors recommend treatment with 2'-deoxycoformycin (2'DCF, Pentostatin) 4 mg/m² intravenously every 2 weeks for 3-6 months. ^[27]

Alpha interferon at 2 million U/m² subcutaneously 3 times a week for 12-18 months can be used to salvage relapsed or refractory hairy cell leukemia.

Treatment of hairy cell leukemia in relapse and unresponsive disease

Many patients in the studies were in relapse or were unresponsive to previous therapy, and it is important to differentiate those with classic forms from variant forms of hairy cell leukemia. Patients with classic hairy cell leukemiawho relapse within 2 years after monotherapy should be differentiated from those with a variant form and, if confirmed, should be considered for re-treatment with an alternative purine analog or combination chemoimmunotherapy. ^[28]

Therapy with rituximab alone given in 4 or 8 weekly courses shows responses less impressive than combination therapy with a purine analog, which is effective in patients who relapse after initial monotherapy. However, there are no randomized trials to conclusively prove that combination chemoimmunotherapy is more effective than monotherapy and that simultaneous purine analog therapy is better than delivering them in series.

Splenectomy was the first standard treatment modality for hairy cell leukemia and was used commonly in the past, but effective medical therapy is currently available and has replaced splenectomy as the first-line treatment

Splenectomy is currently reserved for patients whose conditions fail to respond to systemic therapy or for those with bleeding from thrombocytopenia. Splenic size does not predict response to splenectomy. Patients undergoing splenectomy require appropriate vaccination.

Laparoscopic splenectomy has decreased the morbidity and duration of the postsurgical recovery period.

Although splenectomy does not produce pathologic remissions in the bone marrow, the peripheral blood cell counts improve in all three cell lines in approximately 40-70% of patients. This response occurs rapidly and usually lasts for a median of 20 months in approximately two thirds of patients, with an overall survival rate of 70% in 5 years.