History of Hairy Cell Leukemia

In 1958, Dr. Bouroncle described the multiple features of hairy cell leukemia, firmly establishing this disease as a unique clinical entity. The malignant cells were identified predominantly in the bone marrow, spleen and other tissues. The morphologic description (referring to the form and structure) of this malignant cell was so unique that it was subsequently called “hairy cell leukemia” consistent with the serrated border of the cytoplasm. While the origin of this malignant cell was often debated, it has ultimately been recognized as a B-cell malignancy with a very distinctive immunophenotypic profile.

For the latter part of the past century, the diagnosis was made by describing these leukemic cells in the peripheral blood and the bone marrow. Classic hairy cell leukemia has been differentiated from the less common variant form of this leukemia, which is now known to be a completely separate clinical entity. The leukemic presentation of the variant form of this disease may be associated with bone marrow failure and significant splenomegaly, but the diagnostic markers differ from the classic form of the disease as does the clinical course and response to therapy.

In 2011, Dr. Tiacci and colleagues described the presence of BRAFV600E mutation in leukemic cells from almost every patient with the classic form of hairy cell leukemia. In sharp contrast, this mutation is missing in the variant form of the disease. This observation has provided diagnostic accuracy as well as a novel therapeutic target for patients with the classic form of the disease. In patients who have been unresponsive to standard effective therapy for classic hairy cell leukemia, clinical responses have been observed in patients treated with BRAFV600E inhibitors. Both vemurafenib and dabrafenib have been reported to induce remissions in patients with relapsed or refractory disease.

In the 1950’s, Bouroncle and colleagues reported that the classic form of hairy cell leukemia had a variable chronic course, and the overall survival was in the range of 4 to 6 years. The patient bone marrow was routinely very fibrotic and involved with the leukemic cells, making tolerance to standard cytotoxic agents very challenging. Consequently, splenectomy became the therapy of choice to correct the “cytopenias” that frequently complicated the clinical course for these patients. While splenectomy improved the blood counts, the response was usually limited.

In 1984, Quesda and colleagues reported the remarkable results with daily alpha interferon. Despite symptoms related to the use of this biologic agent (e.g., fatigue and influenza-like symptoms), the improvement in hematologic parameters was dramatic. Granulocyte numbers improved both in the bone marrow and the peripheral blood. Splenomegaly gradually improved as the blood counts responded over several months. While more than 80% of patients achieved a response to alpha interferon, less than 20% achieved a complete remission. Furthermore, responses were in general short-lived. In the same period, a report by Spiers showed that pentostatin was capable of inducing a complete remission in a limited number of patients with hairy cell leukemia. Shortly thereafter, other investigators showed that durable complete remissions could be achieved with lower doses of pentostatin. In a large randomized trial, Grever showed that pentostatin produced complete remission in more than 75% of patients and was markedly more effective than alpha-interferon.

In 1990, Piro and colleagues showed that very promising responses could also be achieved with a seven-day intravenous infusion with cladribine. These responses were sustained. While the complete remission rate was reported to be greater than 90%, the rate of febrile neutropenia was higher with cladribine compared to pentostatin. This raised the possibility that pentostatin might be less likely to induce treatment-related infection. Both agents have now been confirmed as highly effective front-line therapy for newly diagnosed patients with hairy cell leukemia.

Despite the success and the impact of using either purine nucleoside analog, some patients will either relapse or be unresponsive to the initial induction therapy.

Moxetumomab pasudotox (LUMOXITI), an anti-CD22 immunotoxin, was approved by the U.S. Food and Drug Administration (FDA) in September 2018 for the treatment of adult patients with hairy cell leukemia who received at least two prior systemic therapies, including treatment with a purine nucleoside analog.

Exploration and further evaluation of alternative therapy options will continue to be important to achieve durable complete remission for all patients with hairy cell leukemia.