Hairy Cell Leukemia
Minimal Residual Disease
There is currently no accepted standard for minimal residual disease (MRD) monitoring in HCL. While detection of MRD has been clearly associated with increased risk of disease progression, cHCL cells typically do not circulate in the peripheral blood, limiting the use of peripheral blood immunophenotyping for quantitative MRD assessment. For quantitative monitoring of marrow involvement by HCL, immunohistochemical staining of the bone marrow core biopsy is usually required. Staining may be performed for CD20, or, in patients who have received anti-CD20 therapy, DBA.44, VE-1, or CD79a. There is currently not a consensus regarding what level of disease involvement constitutes MRD. One group studied this issue and found that relapse could be predicted by evaluating MRD by percentage of positive cells in the marrow by immunohistochemical staining, with less than 1% involvement having the lowest risk for disease relapse and greater than 5% having the highest risk for disease relapse.25 A recent study evaluated MRD patterns in the peripheral blood of 32 cHCL patients who had completed frontline therapy. This group performed flow cytometry on the peripheral blood of patients at 1, 3, 6, and 12 months following therapy. All patients had achieved a complete response with initial therapy and peripheral blood MRD negativity at the completion of therapy. At a median follow-up of 100 months post therapy, 5 patients converted from peripheral blood–MRD negative to peripheral blood–MRD positive, and 6 patients developed overt disease progression. In all patients who progressed, progression was preceded by an increase in detectable peripheral blood MRD cells.26 Although larger studies are needed, peripheral blood flow cytometric monitoring for MRD may be a useful adjunct to predict ongoing response or impending relapse. In addition, newer, more sensitive methods of disease monitoring may ultimately supplant flow cytometry.
Risk Stratification
Although much progress has been made in the risk stratification profiling of hematologic malignancies in general, HCL has unfortunately lagged behind in this effort. The most recent risk stratification analysis was performed in 1982 by Jansen and colleagues.27 This group of researchers performed a retrospective analysis of 391 HCL patients treated at 22 centers. One of the central questions in their analysis was survival time from diagnosis in patients who had not yet undergone splenectomy (a standard treatment at the time). This group consisted of a total of 154 patients. As this study predated modern pathological and molecular testing, clinical and laboratory features were examined, and these mostly consisted of physical exam findings and analysis of the peripheral blood. This group found that several factors influenced the survival of these patients, including duration of symptoms prior to diagnosis, the degree of splenomegaly, hemoglobin level, and number of hairy cells in the peripheral blood. However, because of interobserver variation for the majority of these variables, only hemoglobin and spleen size were included in the proportional hazard model. Using only these 2 variables, the authors were able to determine 3 clinical stages for HCL (Table 1). The stages were found to correlate with median survival: patients with stage 1 disease had a median survival not reached at 72 months, but patients with stage 2 disease had a median survival of 18 months, which decreased to only 12 months in patients with stage 3 disease. 
Because the majority of patients with HCL in the modern era will be diagnosed prior to reaching stage 3, a risk stratification system incorporating clinical features, laboratory parameters, and molecular and genetic testing is of considerable interest and is a subject of ongoing research. Ultimately, the goal will be to identify patients at higher risk of early relapse so that more intensive therapies can be applied to initial treatment that will result in longer treatment-free intervals.
,Treatment
Because there is no curative treatment for either cHCL or vHCL outside allogeneic transplantation, and it is not clear that early treatment leads to better outcomes in HCL, patients do not always receive treatment at the time of diagnosis or relapse. The general consensus is that patients should be treated if there is a declining trend in hematologic parameters or they experience symptoms from the disease.24 Current consensus guidelines recommend treatment when any of the following hematologic parameters are met: hemoglobin less than 11 g/dL, platelet count less than 100 × 103/µL, or absolute neutrophil count less than 1000/µL.24 These parameters are surrogate markers that indicate compromised bone marrow function. Cytopenias may also be caused by splenomegaly, and symptomatic splenomegaly with or without cytopenias is an indication for treatment. A small number of patients with HCL (approximately 10%) do not require immediate therapy after diagnosis and are monitored by their provider until treatment is indicated.
