Leukemia & Lymphoma, June 2011; 52(S2): 34–37
Alternative methods of cladribine administration
FRANCESCO LAURIA, EMANUELE CENCINI, & FRANCESCO FORCONI Ematologia e Trapianti, Universita
` di Siena & AOUS, Siena, Italy
Abstract Nucleoside derivative cladribine treatment in hairy cell leukemia (HCL) is a rare example of treatment success in cancer. In fact, HCL is generally responsive to single-agent cladribine and only a minority of patients are refractory. Cladribine was originally administered intravenously as a continuous infusion at a dose of 0.1 mg/kg/day for 7 consecutive days. Subsequently cladribine has been administered intravenously, as a 2 h infusion for 5 consecutive days or weekly for 7 weeks, or subcutaneously. These regimens are all very effective but often show relevant toxicity. The subcutaneous route is easier to administer and may increase compliance of the patient. We have had the opportunity to investigate the efficacy and toxicity of subcutaneous cladribine given at the dose of 0.1 mg/kg/day for 5 or 7 days as a single course in newly diagnosedHCLrequiring treatment, in an ongoing Italian multicenter clinical trial. Overall responses have been no different in the two arms, while a much lower infection rate was observed when cladribine was given at the lowest dose. Subcutaneous administration may be deemed a very convenient route since it does not require hospitalization. A reduced dosage of cladribine may also be advantageous since it may be associated with reduced toxicity and may set the dose needed for combinations with antibody treatments.
Keywords: Hairy cell leukemia, therapy, cladribine
Introduction
Hairy cell leukemia (HCL) was described for the first time as a distinct clinical and pathological entity by Bouroncle et al., who referred to it as ‘leukemic reticuloendotheliosis’ [1]. From that time until the advent of interferon-a (IFN-a), several treatments, including androgens, lithium, corticosteroids, splenic irradiation, chlorambucil, or cyclophosphamide, were used, but all proved scarcely effective. Only splenectomy demonstrated some efficacy on disease, but survival was still unsatisfactory, with a median of only 5 years [2]. After the introduction of IFN-a in 1983 and shortly after that of the nucleoside derivatives, pentostatin and cladribine, treatments have become effective, and disease prognosis has dramatically changed [3]. Among the purine analogs, cladribine efficacy was first described in 1990 by Piro et al., who observed lasting responses in a dozen patients treated with this compound [4].
Mechanism of action of cladribine
The purine analog cladribine exerts its antineoplastic function by acting on the adenosine deaminase (ADA) cascade [5]. ADA is an enzyme predominantly expressed in lymphoid cells and plays an important role in the differentiation of both B and T cells. Unlike pentostatin, cladribine does not inhibit ADA, but is highly resistant to the deaminating enzyme due to the introduction of an additional hydrogen atom in position 2 of the purine ring [5]. Cladribine enters the lymphoid cells where it is phosphorylated by a deoxycytidine kinase, creating mono-, di-, and tripho- sphate deoxynucleotides. The phosphorylated deox- ynucleosides accumulate at high concentrations in the cells and are incorporated into the DNA, leading to DNA breaks and subsequent activation of two enzymatic systems: (a) a poly(ADP-ribose) synthetase that consumes cellular nicotinamide adenine dinu- cleotide (NAD) and adenosine triphosphate (ATP);
Correspondence: Francesco Lauria, MD, Sezione di Ematologia e Trapianti, Dipartimento di Medicina Clinica e Scienze Immunologiche, Universita AOUS, Viale Bracci, 53100 Siena, Italy. Tel: þ39-0577-586798. Fax: þ39-0577-586185. E-mail:
lauria@unisi.it
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.570395
` di Siena,
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