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Division of Hematology and Oncology
Division of Hematology and Oncology
Scripps Cancer Center
La Jolla, CA
Hairy cell leukaemia (HCL), an indolent lymphoproliferative disease, has gained significant attention in the past two decades notwithstanding its uncommon occurrence. This is due to its peculiar pathology and the significant therapeutic advances made in its treatment. Patients with HCL achieve a life expectancy approaching that of the general population. In this review, recent major developments in the treatment of HCL, as well as possible future research directions, are outlined.
The nosologic entity of HCL is manifested by the proliferation of abnormal lymphocytes, with characteristic irregular cytoplasmic projections, in multiple organ systems, most notably the bone marrow and spleen (see Figure 1). This ultimately leads to the development of reactive marrow fibrosis, cytopenias and splenomegaly. HCL is a chronic, albeit progressive, disorder, with a median age at diagnosis of 52 years. The male–to–female incidence ratio is 4:1, and the highest incidence is among males of Ashkenazi Jewish descent. In the USA, HCL is diagnosed in approximately 600 patients annually, accounting for only 2–4% of all adult leukaemias.
Treatment of HCL
The early initiation of treatment has not been shown to change the natural history of this disease, and, therefore, therapeutic intervention is usually not recommended until significant anaemia (haemoglobin <10g/dl), thrombocytopenia (platelet count <100 ¥ 10(9)/l), neutropenia (absolute neutrophil count (ANC) <1 ¥ 10(9)/l), morbid splenomegaly, bulky lymphadenopathy, serious infections or systemic symptoms develop.
Before the advent of effective systemic agents, the median overall survival of HCL patients was only 53 months.(1) Historically, splenectomy was the principal treatment, leading to improvement in blood parameters in approximately 50% of patients.(2) During the 1980s, interferon (IFN)-alpha2b was introduced; however, it mostly induced partial responses (PRs), with complete responses (CRs) achieved in only a minority of patients.(3) Currently, IFN is used in clinical situations where serious concurrent infections limit the feasibility of delivering immunosuppressive medications, and occasionally in cases of refractory disease.
The advent of purine nucleoside analogues in the treatment of HCL dates back to 1983.(4) Two agents, pentostatin and cladribine, have since become well-established first-line therapeutic options. Pentostatin is administered at a dose of 4mg/m(2) intravenously (IV) every other week for a period of 3–6 months, until maximal response is obtained. This agent has shown efficacy in both first-line and IFN-refractory settings, achieving five- and 10-year survival rates of 90% and 81%, respectively.(5,6) Caution is advised, particularly in patients with pre-existing bone marrow compromise, given the potential for pentostatin to induce severe myelosuppression.(7) In 1987, cladribine was first administered to HCL patients who had relapsed after splenectomy, with durable CRs being achieved following only one single seven-day IV course at 0.1mg/kg/day.(8) Overall, the incidence and duration of myelo- and immunosuppression induced by cladribine compare favourably with those induced by pentostatin.(7,9,10)
The series with the longest follow-up after cladribine administration documented a CR in 95% and a PR in 5% of HCL patients, with nine-year overall survivals of 97%.(11) The continuous IV infusion schedule for cladribine was selected based on the preclinical data of time- dependent lymphocytotoxicity of this agent, requiring prolonged incubation to achieve maximal cell kill.(12) This cladribine regimen continues to be a practice standard, and, although other investigators reported promising results using easier and more convenient subcutaneous and bolus IV routes, the long-term follow-up data to confirm their equivalence to continuous IV schedule is lacking.(13,14) Although both pentostatin and cladribine target the same adenosine deaminase (ADA) enzyme, their mode of action is different, which may explain their apparent lack of cross-resistance. (11,15) Pentostatin acts as a tight-binding inhibitor of ADA, and, therefore, response to this agent appears to be related to the intracellular level of this enzyme. The activity of cladribine is dependent on the ratio of deoxycytidine kinase (dCK) and 5′-nucleotidase (5′-NT), the phosphorylating and dephosphorylating enzymes in the purine metabolic pathway. No randomised controlled trials comparing these two agents have been performed to date.
Novel immunotherapeutic compounds used in the treatment of HCL include rituximab and the recombinant immunotoxins LMB-2 and BL22. These agents are specifically designed to target, respectively, CD20, CD25 and CD22 antigens, all of which are commonly expressed on HCL cells. Response rates to rituximab, as reported in the two largest series of relapsed or refractory HCL, range from 25% to 80%, thus indicating single-agent activity in this setting.(16,17) Both recombinant immunotoxins contain a truncated form of Pseudomonas exotoxin fused to a variable domain of either anti-Tac (anti-CD25), as is the case in LMB-2, or the monoclonal antibody to CD22, as in BL22. Both agents have demonstrated significant activity in cladribine-refractory HCL patients.(18,19) In a dose-escalation trial of BL-22, 69% of patients achieved CR, a truly remarkable response rate for a purine analogue-resistant HCL patient population.(19) However, in two out of three patients retreated with BL-22, haemolytic–uraemic syndrome, a potentially life-threatening complication, developed. Table 1 presents HCL treatment results in selected series of HCL patients.
Conclusion and future directions
Even though significant advances have been made in the treatment of HCL, the time-to-treatment-failure curve for purine analogue-treated patients does not achieve a plateau, and newer immunohistochemical and PCR techniques still detect minimal residual disease (MRD) in bone marrow samples of patients in apparent CR. This indicates the palliative nature of the treatment, with failure of complete disease eradication and, thus, cure.(11,20) Recent data have raised the possibility of the presence of MRD and an increased risk of relapse in complete responders.(21) The very low rate of MRD with the use of newer immunotherapeutic agents, such as BL22, is appealing and warrants further investigation to develop a curative strategy.(19) Other treatment modalities, such as nonmyeloablative allogeneic bone marrow transplantation, may also find application in selected patients with advanced, multiply refractory HCL.