Chapter 56: Hairy Cell Leukemia

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

Blood cytopenias and marrow reticulin fibrosis are frequent features.

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

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

The male-to-female ratio is approximately 4:1.

The median age at presentation is approximately 55 years.

There is a bimodal peak incidence by age with a mode at approximately age 30 and at age 55.

More than 90% of patients are of European descent.

Disease is rare in persons of African or Asian descent.

No exogenous causes have been established.

A mutation in BRAF (ie, BRAF V600E) is found in virtually all cases. This mutation is not found in cases of variant hairy cell leukemia.

Hairy cells are B cells in a late (preplasma cell) stage of development.

Neoplastic B cells have clonal immunoglobulin gene rearrangements.

Neoplastic B cells express pan-B–cell markers (eg, CD19, CD20, and CD22) and the plasma cell marker prostate cancer antigen-1.

Neoplastic B cells express additional surface antigens that are uncommon on B lymphocytes (eg, CD11c, CD25, and CD103).

Neoplastic B cells secrete cytokines that may impair normal hematopoiesis (eg, tumor necrosis factor-α).

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

Fatigue, weakness, and weight loss may occur (25%).

Bleeding or infection may be present (25%).

Some patients are found incidentally to have abnormal blood count and/or splenomegaly (25%).

Painful bony lesions rarely occur (3%).

Splenomegaly exists in 90% 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.

Anemia is present in three-fourths of patients.

Eighty percent of patients have absolute neutropenia and monocytopenia.

Severe neutropenia (< 0.5 × 10⁹/L) is found in 30% of patients.

Severe monocytopenia is hallmark of the disease.

Thrombocytopenia occurs in about 75% of patients.

Moderate to severe pancytopenia is found in approximately 70% of patients.

Careful examination of the blood by light microscopy identifies hairy cells in 80% of patients (Figure 56–1).

Liver function test abnormalities occur in 19% of cases, azotemia in 27%, and hyperglobulinemia in 18%, 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% 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) (Figure 56–1).

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.

Ribosomal-lamellar cytoplasmic complexes are seen on electron microscopy in about 50% of patients (Figure 56–2).

Cytoplasm stains strongly positive for tartrate-resistant acid phosphatase (TRAP) in approximately 95% 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 (Figure 56–3).

Cytogenetic abnormalities in hairy cell leukemia are very diverse and occur in about 50% of patients, often involving chromosome 5 (eg, 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, such as the following:

— Primary myelofibrosis

— Mast cell disease

Hairy cell leukemia can be differentiated from other lymphoproliferative diseases via its clinical and laboratory features (Table 56–1).

Hairy cell leukemia variant:

— Does not have the BRAF V600E mutation

— More often presents with high white blood cell counts (often > 100 × 10⁹/L)

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

— TRAP staining that is often negative or only weakly positive

— Not associated with neutropenia or monocytopenia

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

— Lack of ribosomal-lamellar complex on electron microscopy

Other B-cell lymphoproliferative disorders:

— Chronic lymphocytic leukemia (see Chap. 55)

— B-cell prolymphocytic leukemia (see Chap. 55)

— Splenic lymphoma with circulating villous lymphocytes (see Chap. 63)

— Lymphocytosis, which is more common

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

— TRAP staining that is either negative or weakly positive

Table 56–2 provides guidelines to management of a patient with hairy cell leukemia.

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

— Symptomatic splenomegaly or lymphadenopathy

— Anemia (hemoglobin level < 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

Cladribine (2-chlorodeoxyadenosine) is the treatment of choice for hairy cell leukemia.

— This purine analog is given as a 7-day continuous intravenous infusion at 0.1 mg/kg per day. (Successful subcutaneous, oral, and weekly dosing has been reported.) (See Table 56–2 for alternative schedule of administration.)

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

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

— In a subsequent study of 207 patients monitored for at least 7 years after cladrabine treatment, 95% had achieved a complete response and 5% a partial response after a single 7-day course. The overall survival at 108 months was 97% 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):

— This purine analog inhibits adenosine deaminase.

— It is a good second choice drug for patients unresponsive or refractory to cladrabine.

— The drug is 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, and conjunctivitis

• Reversible renal dysfunction

• Mild hepatic toxicity

• Depletion of CD4⁺ cells

Interferon-α (IFN-α):

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

— IFN is not curative; 50% 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.

— IFN is not as effective as purine analogs.

— 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.

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

— A proportion (25%–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 is fused to a Pseudomonas exotoxin.

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

— It may be associated with a reversible hemolytic uremic syndrome in a minority of patients.

— Vemurafenib is a BRAF inhibitor to which patient’s in relapse have a high response rate.

Splenectomy

— This procedure is not curative.

— Current indications:

• Massive, painful, and/or ruptured spleen

• Pancytopenia and an active infection with opportunistic pathogen (eg, 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):

— This may ameliorate neutropenia.

— It is an adjunct to therapy in cases of infection.

Radiation

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

With cladribine treatment, patients may be considered curable, with progression free survival rates as high as of 95% at 4 years.

Remissions of over 10 years duration are common.

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

Minimal residual disease can be found using immunohistochemistry and/or flow cytometry in about 35% of long-term responders (median disease-free survival 16 years), but its presence does not necessarily predict for relapse because very long-term responders are as likely as not to have minimal residual disease by very sensitive techniques to identify marrow hairy cells. It is not clear that immediate therapy improves results.

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

Infections, including by opportunistic organisms, that were the cause of death in more than 50% of patients prior to the availability of cladrabine, are now uncommon.