Hairy cell leukemia (HCL) is a relatively rare chronic B-cell malignancy that involves the bone marrow, spleen, and peripheral blood. The complete blood count may reveal pancytopenia including monocytopenia. Median age at diagnosis is approximately 55. Poor prognostic features, while somewhat variable in the literature, may include age, hemoglobin less than 10, platelets less than 100, ANC less than 1000, the presence of lymphadenopathy, and massive splenomegaly. Differential diagnosis includes other B-cell lymphoproliferative disorders, including splenic marginal zone lymphoma. A distinct entity is known as hairy cell leukemia variant (HCL-V), which is biologically unique from HCL also exists. Response to typical HCL in this disease is poor. The variant can be identified by immunophenotypic differences, lack of BRAF mutation, and lack of monocytopenia.
HCL accounts for 2% of all leukemias with approximately 1000 new cases being reported in the United States each year.
The etiology of hairy cell leukemia is not well elucidated. However, previous exposure to various chemicals may play a role in its development. Most cases are postulated to be derived from V600E BRAF gene mutation of late activated memory B cells.
Hairy cell leukemia is a rare neoplasm representing 2% of lymphoid leukemias. Median age at diagnosis is 55 years old. Although it may occur in younger individuals, it is almost never seen in children. Males are disproportionately affected compared to females, with a ratio of 4:1.
As a lymphoproliferative neoplasm, Hairy cell leukemia is a clonal disorder. The relatively recent discovery of the presence of the V600E BRAF mutation in the vast majority of cases of classic Hairy cell leukemia has suggested that the pathogenesis of this disorder lies in the RAS-RAF-MAPK signaling pathway. Constitutive activity of this pathway leads to increased cellular proliferation and survival, and, ultimately, malignancy. A recent study by Sascha Dietrich et al. also found CDKN1B inactivation in 16% of patients with classical HCL. It is the second most common mutated gene in HCL.
Diagnosis of HCL is based on morphological evidence of hairy cells under microscopic examination. The HCL cell is a mononuclear cell that is usually 1 to 2 times the size of a mature lymphocyte. HCL cells can be identified in Romanowsky-stained peripheral blood films from approximately 90% of patients as mononuclear cells that are usually 1 to 2 times the size of a mature lymphocyte. The nuclei are most commonly ovoid but may be round, oval, or horseshoe-shaped. The cytoplasm is variable in amount but usually abundant, pale blue to blue-gray, and occasionally described as "fluffy" or "hairy." The hairy projections are more easily visualized under the electron microscope.
Affected patients often have non-specific symptoms including fatigue and weakness, as well as symptoms related to cytopenias and splenomegaly. Eighty percent of patients will have significant cytopenias on presentation, with severe pancytopenia in less than 10%. While splenomegaly is a predominant feature, massive, symptomatic splenomegaly is less frequent, perhaps due to earlier detection on routine complete blood count (CBC). Autoimmune thrombocytopenia and hemolytic anemia can occur along with hairy cell leukemia, rarely. Infectious complications are common, due to both the underlying immunosuppression from cytopenias and myelosuppressive therapy.
Diagnosis is achieved by studies on peripheral blood, including flow cytometry and review of peripheral smear, along with bone marrow biopsy. A “dry tap,” or, inability to perform bone marrow aspiration is frequently encountered with hairy cell leukemia (although not with HCL-V). The hairy cell has characteristic-appearing mononuclear cells which are typically large with circumferential hair-like cytoplasmic projections and a round, well-defined nucleus. The flow cytometry markers positive in hairy cell leukemia include CD11c, CD25, CD103, and CD123, along with typical B-cell markers such as CD19, CD20, or CD22. The cyclin-d1 expression is usually present, but it is weak or focal (in contrast to mantle cell lymphoma). HCL-V is negative for CD25 and CD123. BRAF-mutation V600E is seen in nearly all cases of classic hairy cell leukemia (although it is not present in HCL-V). CT should be considered to assess the degree of lymphadenopathy.
Given its incurable nature, hairy cell leukemia treatment is reserved for symptomatic patients, including significant fatigue, symptomatic splenomegaly, and significant cytopenias (hemoglobin less than 12 g/dL, platelets, 100000/mcL, ANC less than 1000/mcL). Asymptomatic individuals should be monitored closely for disease progression with history and physical and CBC approximately every 3 to 6 months.
Cladribine and pentostatin, 2 purine analogs, are the first-line treatment for hairy cell leukemia. They are equally effective in inducing and maintaining remission. Nonetheless, cladribine is regarded as first-line chemotherapy among most hematologists due to its favorable toxicity profile. A single course of cladribine induces complete response in approximately 90% of individuals after one cycle (5 to 7 days). It is important to note that these patients will be immunosuppressed for many months following therapy, and attention to possible infectious complications is critical. A recent meta-analysis conducted by Andrasiak et al. showed that the most effective therapy in patients who are treatment naive and in the first relapse was cladribine with rituximab maintenance. Vemurafenib was also shown to be similarly efficacious; however, it is usually used for refractory or progressive cases.
Interferon alpha is the treatment of choice during pregnancy when treatment is warranted. It may be preferred for the initial treatment in patients with severe pancytopenia and/or active infection to improve blood counts and allow for subsequent therapy with purine analogs. However, patients with HCL who express the CD5 antigen appear to respond poorly to IFN-a.
Splenectomy may be considered in patients with symptomatic massive splenomegaly, severe pancytopenia due to splenic sequestrations and as a temporizing measure in symptomatic pregnant women.
Repeat bone marrow biopsy should be performed after treatment to confirm complete remission. Complete remission is defined as the absence of hairy cells in blood and bone marrow, resolution of splenomegaly, and recovery of peripheral blood counts (Hgb greater than 12, platelet greater than 100, ANC greater than 1500). Partial response is defined as normalization of peripheral blood counts along with 50% decrease in splenomegaly, and less than 5% of circulating hairy cells remain. Currently, the clinical implications for minimal residual disease (MRD) are poorly defined. Many patients MRD will still have prolonged, complete hematologic remissions.
Relapsed disease can be treated with either another course of purine analog (if relapse is more than 1 year from initial treatment); however, response rates are often lower, and remissions shorter after relapse. Many other options for relapsed or refractory disease exist, including a combination of cladribine or pentostatin with rituximab, fludarabine alone or in combination with rituximab, bendamustine, and interferon alpha. The BRAF mutation in hairy cell leukemia can be targeted by the oral BRAF inhibitor vemurafenib, which has been shown to be efficacious in both the relapsed and refractory settings.
Supportive care measures such as antimicrobial prophylaxis for viral and pneumocystis pneumonia should be considered for those with significant cytopenias. Transfused blood products, if necessary, should be irradiated to prevent transfusion-associated graft-versus-host disease.
Differential diagnoses include:
Many investigational therapeutic agents are underway for treatment of hairy cell leukemia. At least 3 monoclonal antibodies, directed against CD22, CD20, or CD25, have been evaluated in the treatment of resistant or relapsed HCL. However, except for rituximab, the anti-CD20 antibody, the other monoclonal antibodies are still considered experimental at this point.
The median survival is usually 4 years without treatment. VH4-34 positive HCL cases are associated with poor prognosis.
Several studies have reported cases of secondary malignancies in patients with hairy cell leukemia. It could be explained by the immunosuppression caused by the disease itself or the use of chemotherapeutic agents.