variant form of the disease, representing about 60-75 new cases of HCL-V each year in the U.S. While classic HCL primarily affects men, HCL-V is more evenly divided between males and females. While the disease can appear at any age, the median age at diagnosis is over 70. Similar to B-cell prolymphocytic leukemia (B-PLL) in chronic lymphocytic leukemia, HCL-V is a more aggressive disease. Historically, it has been considered less likely to be treated successfully than is classic HCL, and remissions have tended to be shorter. The introduction of combination therapy with concurrent rituximab and cladribine therapy, though, has shown excellent results in early follow-up. As of 2016, this therapy is considered the first-line treatment of choice for many people with HCL-V. Many older treatment approaches, such as interferon-alpha, the combination chemotherapy regimen "CHOP", and common alkylating agents such as cyclophosphamide, showed very little benefit. Pentostatin and cladribine administered as monotherapy (without concurrent rituximab) provide some benefit to many people with HCL-V, but typically induce shorter remission periods and lower response rates than when they are used in classic HCL. More than half of people respond partially to splenectomy. HCL-V differs from classic HCL principally in these respects: Higher white blood cell counts, sometimes exceeding 100,000 cells per microliter A more aggressive course of disease requiring more frequent treatment Hairy cells with an unusually large nucleolus for their size Production of little excess fibronectin produced by classic hairy cells to interfere with bone marrow biopsies Low or no cell-surface expression of CD25 (interleukin-2 [IL-2] receptor alpha chain, or p55). Low levels of CD25, a part of the receptor for a key immunoregulating hormone, may explain why HCL-V cases are generally much more resistant to treatment by immune-system hormones. HCL-V, which usually features a high proportion of hairy cells without a functional p53 tumor suppressor gene, is somewhat more likely to transform into a higher-grade malignancy. A typical transformation rate of 5-6% has been postulated in the UK, similar to the Richter's transformation rate for splenic lymphoma with villous lymphocytes (SLVL) and CLL. Among HCL-V patients, the most aggressive cases normally have the least amount of p53 gene activity. Hairy cells without the p53 gene tend, over time, to displace the less aggressive p53(+) hairy cells. Some evidence suggests that a rearrangement of the immunoglobulin gene VH4-34, which is found in about 40% of HCL-V patients and 10% of classic HCL