Chapter 57: Hairy Cell Leukemia

B-lymphocyte malignancy that principally involves the marrow and spleen.

Reactive marrow fibrosis and blood cytopenias are frequent features.

Irregular cytoplasmic projections on neoplastic B lymphocytes (which gives the disease its name), most striking when examined as a wet preparation by phase microscopy.

Estimated that about 700 cases per year occur in the United States (approximately 2% of all leukemias).

Male:female ratio approximately 4:1.

Median age at presentation approximately 50 to 55 years.

No exogenous causes established.

Disease is rare in persons of African or Asian descent.

Hairy cells are B cells in a late (pre-plasma cell) stage of development.

B cells have clonal immunoglobulin gene rearrangements.

Express pan-B–cell markers (e.g., CD19, CD20, and CD22) and the plasma cell marker Prostate Cancer Antigen-1.

Express additional surface antigens that are uncommon on B lymphocytes (e.g., CD11c, CD25, and CD103).

Secrete cytokines that may impair normal hematopoiesis (e.g., tumor necrosis factor-α).

Abdominal fullness/discomfort caused by massive splenomegaly (25%).

Fatigue, weakness, weight loss (25%).

Bleeding or infection (25%).

Found incidentally to have abnormal blood count and/or splenomegaly (25%).

Painful bony lesions (3%).

Splenomegaly in 90 percent of patients (median splenic weight approximately 1300 g).

Infections with common bacteria, viruses, fungi, Mycobacterium kansasii, Pneumocystis jiroveci, aspergillus, histoplasma, cryptococcus, Toxoplasma gondii or other opportunistic organisms, once common, are less frequent because of more effective initial therapy.

Unusual findings include: cutaneous vasculitis, leukoclastic angiitis, erythema nodosum, polyarthritis, and Raynaud phenomenon.

Eighty percent of patients have absolute neutropenia and monocytopenia.

Severe neutropenia (< 0.5 × 10⁹/liter) in 30 percent of patients.

Severe monocytopenia is hallmark of the disease.

Anemia is present in three-quarters of patients.

Moderate to severe pancytopenia found in 67 percent.

Thrombocytopenia in about 75 percent of patients.

Careful examination of the blood by light microscopy identifies hairy cells in 80 percent of patients (Fig. 57–1) and in > 90 percent of patients with flow cytometry.

Liver function test abnormalities in 19 percent, azotemia in 27 percent, and hyperglobulinemia in 18 percent, which may be monoclonal.

Occasionally leukocytosis is present as a result of circulating hairy cells. Extreme leukocytosis (>100 × 10⁹/L) can occur very infrequently, most often seen in the "hairy cell leukemia variant" (see below).

Hairy cells comprise less than 20 percent of lymphocytes in patients with low white blood cell counts, but are the predominant cell in patients whose white blood cell count is greater than 10 × 10⁹/L.

Marrow biopsy shows focal or diffuse infiltrate of leukemic cells with characteristic surrounding halo of pale-staining cytoplasm (the "fried-egg" appearance) and a diffuse fine fibrillar network best appreciated with the periodic acid–Schiff stain (Fig. 57–1).

Marrow is usually hypercellular, but occasionally hypocellular, mimicking aplastic anemia.

Immunohistochemistry with CD22 and CD103 antibodies is more sensitive than morphology in detecting residual neoplastic cells in the marrow.

Diffuse infiltration of splenic red pulp cords and sinuses by hairy cells.

Irregular cytoplasmic projections can be found on light and electronic microscopy.

Ribosomal-lamellar cytoplasmic complexes seen on electron microscopy in about 50 percent of patients.

Cytoplasm stains strongly positive for tartrate-resistant acid phosphatase (TRAP) in approximately 95 percent of hairy cell cases. (This classic test has been replaced by flow cytometry for hairy cell markers.)

Hairy cells most commonly coexpress high levels of CD11c, CD22, CD25, and CD103, but lack of expression of CD21 (Table 57–1).

Cytogenetic abnormalities in hairy cell leukemia are very diverse and occur in about half the patients, often involving chromosome 5 (e.g., trisomy, interstitial deletions, pericentric inversions of chromosome 5).

Hairy cell leukemia should be differentiated from nonlymphoid disorders that can present with pancytopenia, splenomegaly, and marrow fibrosis.

— Primary myelofibrosis.

— Mast cell disease.

Hairy cell leukemia can be differentiated from other lymphoproliferative diseases via its clinical and laboratory features (Table 57–1).

Hairy cell leukemia variant:

— More often presents with high white blood cell counts (often > 100,000/μL).

— Have a higher nucleus-to-cytoplasm ratio than do hairy cell leukemia cells.

— TRAP staining is often negative or only weakly positive.

— Not associated with neutropenia or monocytopenia.

— Hairy cell variant cells are often negative for CD25 and CD103.

— Lack ribosomal-lamellar complex on electron microscopy.

Other B-cell lymphoproliferative disorders:

— Chronic lymphocytic leukemia (see Chap. 56).

— B-cell prolymphocytic leukemia (see Chap. 56).

— Splenic lymphoma with circulating villous lymphocytes (see Chap. 64)

— Lymphocytosis is more common.

— Lymphocytes have more basophilic cytoplasm and generally do not express CD103.

— TRAP staining is either negative or weakly positive.

Approximately 90 percent of patients require treatment at time of diagnosis. Indications include:

— Symptomatic splenomegaly or lymphadenopathy.

— Anemia (Hb level less than 10 g/dL).

— Thrombocytopenia (platelet count <100 × 10⁹/L).

— Granulocytopenia (neutrophil count < 1.0 × 10⁹/L) with recurrent bacterial or opportunistic infections.

— Leukemic phase (white cell count > 20 × 10⁹/L).

— Vasculitis.

— Painful bony involvement.

Cladrabine (2-Chlorodeoxyadenosine) is the treatment of choice for hairy cell leukemia.

— A purine analogue given as a 7-day continuous intravenous infusion at 0.1 mg/kg per day. (Successful subcutaneous, oral, and weekly dosing has been reported.)

— Can induce long-lasting complete responses in greater than 75 percent of patients. Initially, 91 percent have complete response and 7 percent a partial response.

— Sixteen percent of complete responders have evidence of relapse at 48 months. Approximately 90 percent of patients initially treated with cladrabine who relapse will have a complete (62%) or partial response (26%) when retreated with the same drug.

— In a subsequent study of 207 patients monitored for at least 7 years after cladrabine treatment, 95 percent had achieved a complete response and 5 percent a partial response after a single 7-day course. The overall survival at 108 months was 97 percent and the median disease-free duration for all responders was 98 months.

— Notable toxicities of cladrabine:

• Aseptic fever in setting of neutropenia.

• T-cell depletion, particularly CD4⁺ cells.

Pentostatin (2′-deoxycoformycin):

— A purine analogue that inhibits adenosine deaminase.

— A good second choice drug for patients unresponsive or refractory to cladrabine.

— Administered as an intravenous bolus of 4 mg/m² every other week for 3 to 6 months until maximum response as judged by decrease of blood and marrow hairy cells, reduced spleen size, and improvement in normal blood cell counts.

— Complete response rates with pentostatin (~50%) are lower than that achieved with cladribine.

— Pentostatin may not be effective in patients refractory to cladribine.

— Notable toxicities:

• Fever, rash, conjunctivitis.

• Reversible renal dysfunction.

• Mild hepatic toxicity.

• Depletion of CD4⁺ cells.

Interferon-α (IFN-α):

— Complete response rate is 8 percent; 74 percent achieve a partial response.

— Not curative; 50 percent relapse less than 2 years after treatment.

— Usual dosage schedule is 2 × 10⁶ U IFN-α_2b/m² subcutaneously three times weekly for 12 months or 3 × 10⁶ U IFN-α_2a/m² subcutaneously daily for 6 months and decreased to 3 times per week for an additional 6 months.

— Not as effective as purine analogues.

— Toxicity:

• Flu-like symptoms (fever, myalgia, malaise).

• Myelosuppression.

Rituximab

— Hairy cells express CD20 and thus an anti-CD20 monoclonal antibody is rational.

— The responses have been modest but it should be considered in patient's refractory to cladrabine and pentostatin.

— 375 mg/m² intravenously weekly for 4 to 8 weeks.

— A proportion (25 to 75%) of patients has a complete or partial remission, which may be sustained for several years in a proportion of responders. Others relapse and progress.

Anti-CD22 Immunotoxin BL22

— Anti-CD22 fused to a Pseudomonas exotoxin.

— Can induce remissions in a high proportion of patients who are refractory to cladrabine.

— Associated with a reversible hemolytic uremic syndrome in a minority of patients.

Splenectomy

— Not curative.

— Current indications:

• Massive, painful, and/or ruptured spleen.

• Pancytopenia and an active infection with opportunistic pathogen (e.g., Mycobacterium). Splenectomy usually results in marked increase in neutrophil and monocyte count and better response to antimicrobial treatment.

• Failure of systemic chemotherapy.

Granulocyte colony-stimulating factor (G-CSF):

— May ameliorate neutropenia.

— Adjunct to therapy in cases of infection.

Radiation

— Lytic bone lesions can be treated with low-dose irradiation.

With cladrabine treatment considered curable with overall survival rates in excess of 95 percent at 4 years.

Remissions of over 10 years duration common.

Minimal residual disease can be found in about 35 percent of long-term responders (median disease-free survival 16 years) but its presence does not necessarily predict for relapse since very long-term responders are as likely as not to have minimal residual disease by very sensitive techniques to identify marrow hairy cells.

A plateau in relapse has not been reached at over 10 years of remission and, thus, a risk of late relapse exists.

Relapsed patients after first treatment with cladrabine have a high response rate to retreatment with cladrabine or another agent.

Infections, including by opportunistic organisms, the cause of death in over 50 percent of patients prior to the availability of cladrabine, are now uncommon.