Leukemia & Lymphoma, June 2011; 52(S2): 25–28
Hairy cell leukemia: a successful model for experimental therapeutics—pentostatin and new ideas
MICHAEL R. GREVER Department of Pharmacology, The Ohio State University, Columbus, OH, USA
Abstract Hairy cell leukemia (HCL) was once considered an untreatable form of chronic lymphoid malignancy. Based upon the recognition of the importance of adenosine deaminase to the normal B cell survival and proliferation, a hypothesis was developed that temporary inhibition of this enzyme might be therapeutically successful in treating chronic B cell leukemias. Pentostatin was initially explored in patients with refractory chronic lymphocytic leukemia (CLL). Both pentostatin and cladribine, purine nucleoside analogs, have been utilized to successfully treat HCL. The high degree of complete and durable remission observed with either agent resulted in many believing that the treatment of this rare disease had been fully optimized. However, a considerable number of patients will relapse. While tremendous progress has been made in initial management, the issues related to optimal therapy, timing of initiation of treatment, and discovery of novel agents that may be effective in those who have relapsed are important. Investigational agents currently being explored in chronic lymphocytic leukemia may also have benefit for those patients who have relapsed or are resistant to therapy of hairy cell leukemia. Many important questions remain (e.g. importance of minimal residual disease) and will require international collaboration to fully address these unanswered questions. The Hairy Cell Leukemia Consortium was established to address these unanswered questions.
Keywords: Hairy cell leukemia, pentostatin, adenosine deaminase inhibitor
The enormous success in treatment for patients with hairy cell leukemia (HCL) over the past quarter of a century represents a model for experimental ther- apeutic research. While this disease was initially described by Bouroncle and colleagues in 1958, the median survival has progressively improved since 1984 [1,2]. In an extensive analysis of a large population of patients with HCL, Frassoldati et al. showed that prognostic factors including degree of anemia and selection of treatment had a profound impact on outcome. Overall survival markedly improved after 1984. Splenectomy had been the mainstay of therapy for patients with deteriorating blood counts, and standard chemotherapy of that era had largely been a failure in achieving hematologic improvement. The introduction of interferon-a in 1984 was greeted with excitement, as 80% of the patients treated with this agent had hematologic improvement, and 10% achieved a complete remis- sion [3].
In 1972, the observation had been made that
adenosine deaminase (ADA) was essential for the normal development of immune effector cells [4]. Children with a deficiency of this critical enzyme developed severe combined immune deficiency dis- ease. This enzyme is important for normal lympho- cyte proliferation and function as well as monocyte differentiation into macrophages [5,6]. In exploring the impact of a pharmacologic inhibitor of this enzyme (pentostatin), we identified that temporary inhibition of ADA in vitro resulted in leukemic cell death in malignant cells from patients with chronic lymphocytic leukemia (CLL) [7]. In addition, we confirmed that the administration of pentostatin to patients with advanced CLL produced responses despite extensive prior therapy [8]. We utilized a biochemical assay to document the kinetics of ADA enzyme inhibition in circulating leukemic cells from patients treated with pentostatin combined with pharmacologic measurement of plasma drug levels
Correspondence: Michael R. Grever, MD, Chairman & Charles A. Doan Professor of Medicine, Professor of Pharmacology, The Ohio State University, Columbus, OH, USA. E-mail:
michael.grever@
osumc.edu
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.577851
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