Hairy Cell Leukemia Treatment & Management

Patients with hairy cell leukemia (HCL) who have stable peripheral blood cell counts may be observed closely on a watch-and-wait program that entails at least quarterly blood cell counts and physical examinations. ^[23]  Approximately 10% of  patients, usually elderly men with moderate splenomegaly and mild decrease in blood counts, remain asymptomatic and never require therapy.

If the blood cell counts show a sustained decline or the patient becomes symptomatic (ie, develops fatigue or splenomegaly), then therapy with a purine analogue is started before the counts decline to dangerously low levels. The purine analogues used are cladribine (2-chlorodeoxyadenosine [2-CdA]; Leustatin) and pentostatin (2-deoxyformycin [2'-DCF]; Nipent).

Blood cell counts may worsen temporarily after the initiation of either cladribine or pentostatin, so intervention should definitely begin before these hematologic parameters have deteriorated to 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 regarding the use of either pentostatin or cladribine alone for hairy cell leukemia suggest that these agents are equally effective in terms of response rate and remission duration. ^[9]  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.

Substantial improvement in overall survival has been reported with initial use of either agent. Although close monitoring for late adverse effects of therapy is necessary, patients with hairy cell leukemia may now live as long as they would have without this diagnosis. ^[24] The progress in treatment changed the natural history of this disease. Although the best way to initiate therapy remains unsettled, there is a consensus that attaining a complete remission is important to reduce the possibility of a late relapse.

In selecting appropriate chemotherapy, the following clinical questions must be considered:

• Is there evidence of active, untreated, ongoing infection?
• Does the patient have a good performance status and adequate renal function?

Although it is prudent to attempt to treat an active infection before starting purine analogue therapy in a patient with hairy cell leukemia, the profound neutropenia and monocytopenia from the disease may force the decision to start antileukemic therapy. Otherwise, the patient may succumb to the infection. However, purine analogues 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. ^{[25, 26]}

The use of granulocyte colony-stimulating factor (G-CSF) can raise the absolute neutrophil count and shorten the period of severe neutropenia in hairy cell leukemia patients receiving cladribine, but routine use has not been shown to offer any clinical advantage. ^[27]

One strategy involves starting treatment 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; this is followed by a definitive purine analog therapy to achieve complete remission. ^[28]  Complete remission rates with interferon only are low, at 11% in patients without infection and 5% in patients with infection

Alternatively, pentostatin may be used. Although complete remission rates are better than with interferon—78% in uninfected patients  and 68% in infected patients—and the frequency of febrile episodes requiring antibiotic therapy is 27%, controlling infection if possible before starting pentostatin is recommended.

Pentostatin is cleared by the kidneys, so kidney function must be carefully monitored during therapy. Patients with a serum creatinine of 1.5 mg/dL or higher should be excluded from receiving the drug. The initial dose is reduced to 2 mg/m² in patients whose performance status is impaired, with subsequent escalation to full-dose therapy if tolerated. Hydration with 1.5 L of fluid is usually given along with each dose of the drug and the serum creatinine is checked before each subsequent infusion.

For more information, see Hairy Cell Leukemia Treatment Protocols.

The standard criteria for initiating therapy for hairy cell leukemia (HCL) 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

The first-line therapy for HCL is cladribine, 0.1 mg/kg/d by continuous intravenous infusion for 7 days. The drug can be administered on an outpatient basis with a pump, after placement of a peripherally inserted central catheter (PICC). ^{[29, 30, 31]}

Growth factors are not routinely given but may be added in patients with febrile neutropenia. Platelet counts usually respond first (in 2-4 weeks), followed by white blood cell counts and neutrophil counts 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 cladribine, 80% of patients obtain a complete remission (CR), and the remainder obtain 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%. ^[32] In addition, 17% of patients had developed another malignancy during that time.

For greater convenience, some groups have given cladribine 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.

In patients with minimal residual disease following treatment with cladribine, observation is currently the standard therapy. Ravandi et al reported that treatment with rituximab resulted in eradication of minimal residual disease in 11 of 12 patients with residual disease following cladribine therapy. ^[33]  Whether this treatment alters the natural history of HCL or prevents relapse is unclear.

For patients with relapsed HCL who have previously been treated with splenectomy, interferon, or pentostatin, retreatment with cladribine in the same manner is indicated, especially if their disease had previously responded to cladribine. In patients previously treated with cladribine, response rates of 50% are typical. ^[34]  In patients with relapsed or refractory HCL who are treated with rituximab, response rates of 50% are reported.

For patients with HCL that is refractory to cladribine, or if relapse occurs after two cycles of cladribine, the authors recommend treatment with pentostatin, 4 mg/m² intravenously every 2 weeks for 3-6 months. ^[35]  Interferon alfa at 2 million U/m² subcutaneously 3 times a week for 12-18 months can also be used to salvage relapsed or refractory HCL.

Another option for relapsed or refractory HCL is moxetumomab pasudotox (Lumoxiti), an anti-CD22 recombinant immunotoxin approved by the US Food and Drug Administration (FDA) in 2018. Approval was based on efficacy and safety data from a single-arm, open-label phase III clinical trial in 80 patients. In this trial, the durable complete response (CR) rate was 30%, the CR rate was 41%, and the objective response rate (CR and partial response) was 75%. Also, 80% of patients achieved hematologic remission. ^[36]

Hyperuricemia may occur during therapy in patients with HCL who have leukocytosis and high tumor burden. Add allopurinol at 300 mg per day orally.

In patients who relapse within 2 years after monotherapy, it is important to differentiate classic HCL from the variant form. If classic HCL is confirmed, the patient should be considered for re-treatment with an alternative purine analogue or combination chemoimmunotherapy. ^[37]

Therapy with rituximab alone, given in 4 or 8 weekly courses, produces responses less impressive than combination therapy with a purine analogue, 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 analogue therapy is better than delivery of treatment in series.

Vemurafnib is a BRAF kinase inhibitor that is approved for use in other diseases that harbor a BRAF V600 mutation. In a multicenter study in Italy and the United States, treatment with vemurafenib (at a dose of 960 mg twice daily) proved effective in patients with relapsed or refractory disease after treatment with a purine analogue. Vemurafenib was given for a median of 16 weeks in the Italian arm and 18 weeks in the US arm. The overall response rates were 96% (25 of 26 patients) after a median of 8 weeks in the Italian cohort and 100% (24 of 24) after a median of 12 weeks in the US cohort. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in Italy and the US, respectively. ^[38]

Bruton tyrosine kinase inhibitors

Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, demonstrated benefit in a multisite phase II study in 37 patients with either classic HCL (28 patients: 76%) or HCL variant (nine patients: 24%). Patients received either single-agent ibrutinib at 420 mg daily (24 patients) or 840 mg daily (13 patients). The overall response rate (ORR) increased from 24% at 36 weeks to 36% at 48 weeks. the best ORR achieved was 54%. The estimated 36-month progression-free survival (PFS) was 73% and the estimated 36-month overall survival (OS) was 85%, with no differences between classic and variant disease. ^[39]  

National Comprehensive Cancer Network (NCCN) guidelines now include the off-label use of ibrutinib as a recommended treatment for progressive disease after relapse/refractory therapy. ^[15]

Splenectomy was the first standard treatment modality for hairy cell leukemia and was used commonly in the past, but effective medical therapy 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 5-year survival rate of 70%.

Hairy cell leukemia is usually indolent and protracted; late relapses occur. Long-term outpatient follow-up is necessary in most patients.

Evaluation of minimal residual disease by posttreatment bone marrow biopsies using anti-CD20 by flow cytometry reveals that 13-51% of patients in apparent CR had minimal residual disease. The presence of minimal residual disease appears to predict clinical relapse. Because a majority of patients respond very well to retreatment (92% response) or salvage treatment (80% response), no evidence supports treatment of minimal residual disease.

Newer therapies, such as the anti-CD20 monoclonal antibody rituximab, have been tested in patients with hairy cell leukemia that was refractory to standard treatment. In studies with small numbers of patients who received rituximab, results ranged from an overall response of 64% with a median duration of response of 14 months, to 100% response with a duration of 73 months, indicating that this form of therapy is active against hairy cell leukemia.