, Volume 46, Issue 5, pp 872-894
Date: 22 Oct 2012

Cladribine

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Abstract

Synopsis

Cladribine (2-chloro-2′-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. In the treatment of hairy cell leukaemia, cladribine has demonstrated excellent efficacy (complete response in 33 to 92% of patients) in noncomparative studies. Cladribine appears to compare favourably with other systemic agents in this indication as it achieves a high degree of efficacy after a single 7-day course, with an acceptable tolerability profile. However, long term data and direct comparative studies with interferon-α and pentostatin (deoxycoformycin) are required to confirm the finite advantages offered by cladribine.

Preliminary results obtained in other indications including chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, cutaneous T cell lymphoma, Waldenström’s macroglobinaemia and acute myeloid leukaemia in children have been sufficiently encouraging to warrant further study. Early pharmacokinetic data suggest that cladribine may be administered by oral and subcutaneous routes, both of which permit convenient outpatient therapy.

Myelosuppression, the dose-limiting toxicity of cladribine, and culture-negativ e fever are the most common adverse effects associated with therapy. However, cladribine appears to be only rarely associated with many of the other adverse effects that characterise antineoplastic therapy. In the weeks post-treatment, there is a small but definite risk of serious infection; infections with a fatal outcome have been reported in a number of studies with cladribine.

In conclusion, preliminary data concerning cladribine have been extremely encouraging. Should early response rates in patients with hairy cell leukaemia be sustained, the efficacy of the drug, together with a short treatment regimen, a favourable tolerability profile, and the possibility of oral therapy, suggest that cladribine is likely to supersede other agents available for this indication.

Pharmacodynamic Properties

Cladribine is an adenosine deaminase (ADA)-resistant analogue of deoxyadenosine. The drug has a broad range of in vitro activity against both lymphoid and myeloid neoplasms [mean IC50 values (drug concentration required to inhibit cell growth by 50% of control) 20 to 87 nmol/L], but possesses little activity against multiple myeloma specimens and many solid tumour cell lines. Monocytes are highly sensitive to cladribine in vitro. Cladribine demonstrates activity against both dividing and nondividing cells, activity that distinguishes it from many other agents, and also has activity in murine models of leukaemia.

The precise mechanism of action of cladribine in either dividing or nondividing cells is unknown. Incorporation of the triphosphate form of cladribine into DNA is thought to be important in arresting cell activity. Cladribine is a potent inhibitor of ribonuclease reductase (IC50 0.11 to 0.28 μmol/L), which also may be involved in its activity. In nondividing cells, it has been suggested that cladribine may induce apoptosis (programmed cell death).

Pharmacokinetic Properties

After a 2-hour intravenous infusion of cladribine 0.14 mg/kg/day, the mean maximum plasma drug concentration was 198 nmol/L. Intracellular concentrations of phosphorylated cladribine derivatives exceed plasma concentrations 128- to 375-fold. Cladribine penetrates into the CSF. The terminal elimination half-life (6.7 hours) is long, which suggests that the drug may be administered intermittently without loss of efficacy. The volume of distribution of cladribine is 9.2 L/kg.

Cladribine has also been administered successfully by both oral and subcutaneous routes; after oral administration in buffer solution, systemic bioavailability was 55%.

Therapeutic Potential

All trials conducted with cladribine to date have been noncomparative in nature and conducted in relatively small numbers of patients. The majority of studies involved the recommended 7-day regimen of intravenous cladribine 0.1 mg/kg/day, administered as a continuous infusion.

The best and most durable response with cladribine has been obtained in patients with hairy cell leukaemia. A complete response was achieved in 33 to 92%, and a partial or complete response in 67 to 100%, of a total of 298 evaluable patients involved in 8 clinical trials. Three relapses only were reported after a median follow-up of 20 to 76 weeks. Previous therapy with splenectomy, interferon-α or a combination of the 2 treatment modalities did not appear to affect the response rate to cladribine.

Cladribine is also being investigated as a second-line agent in chronic lymphocytic leukaemia (CLL). An overall response rate of 44% (4% complete response) was achieved after a median of 2 courses of cladribine therapy in 90 patients with refractory CLL. The median duration of response was 4 months. While some investigators have reported good results in patients with CLL resistant to fludarabine, more recent data have been less encouraging. Given the marked immunosuppression associated with the use of nucleoside analogues, cladribine should be used with caution after fludarabine has failed.

In a total of 73 patients with refractory low- or intermediate-grade non-Hodgkin’s lymphoma, 43 to 50% responded for a median duration of 5 to 6 months to cladribine administered as salvage therapy, 8 to 20% of whom achieved a complete response.

Encouraging results have also been reported in paediatric patients with refractory acute myelogenous leukaemia (AML). Eight of 17 (47%) patients with AML achieved a complete response after treatment with cladribine 8.9 mg/m2/day administered for 5 days; a further 2 patients had a partial remission giving an overall response rate of 59%. A poorer response was achieved in adults with AML and in patients with acute lymphoblastic leukaemia.

In smaller groups of patients, cladribine has also demonstrated efficacy in cutaneous T cell lymphoma, Waldenström’s macroglobinaemia, autoimmune haemolytic anaemia, prolymphocytic leukaemia, and some activity in chronic myeloid leukaemia.

Tolerability

Unlike other antineoplastic agents, cladribine is rarely associated with nausea, vomiting, alopecia, skin rash, or abnormal renal or hepatic function when administered at the recommended dosage. The dose-limiting toxicity of cladribine is bone marrow suppression. In general, myelosuppression is manifested as reversible neutropenia, anaemia and thrombocytopenia after a standard course of cladribine therapy. There have been only isolated reports of pancytopenia. In common with both pentostatin (deoxycoformycin) and fludarabine, cladribine suppresses lymphocytes expressing CD4 or CD8 surface antigens.

Another common adverse effect associated with cladribine is culture-negative fever, which affects 46 to 58% of patients with hairy cell leukaemia. There is a small but definite risk of opportunistic infections in the post-treatment period. Infections have been reported in 10 to 39% of cladribine-treated patients. Serious infections with a fatal outcome have been described in a number of studies.

Dosage and Administration

The recommended regimen for cladribine in hairy cell leukaemia is a single continuous 7-day intravenous infusion at a dosage of 0.09 mg/kg/day (corrected for extinction coefficient). The dosage used in the majority of clinical trials (0.1 mg/kg/day) was standardised originally using the extinction coefficient of chloroadenine which is lower than that of cladribine. Thus, the actual cladribine dose administered was about 87% of that stated; the corrected dosage of cladribine is therefore 0.09 mg/kg/day.

A second course of therapy has been administered in patients who relapse in some trials. The same regimen administered monthly for up to 6 courses can be used to treat patients with CLL, low-grade lymphoma or cutaneous T cell lymphoma resistant to other agents. Antibiotic support should be administered as required. In children with acute myelogenous leukaemia, the recommended maximum tolerated dosage is 8.9 mg/m2/day administered as a 5-day continuous infusion. Caution is required when administering cladribine after or in combination with agents known to cause myelosuppression.

Various sections of the manuscript reviewed by: G. Bonadonna, Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; D.A. Carson, Research Institute of Scripps Clinic, La Jolla, California, USA; B.D. Cheson, Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, USA; E.E. Damasio, First Department of Haematology, San Martino Hospital, Genoa, Italy; A. Delannoy, Service d’Hématologie, Hôpital de Jolimont, Haine-Saint Paul and Cliniques Universitares Saint Luc, Brussels, Belgium; K. Ganeshaguru, Department of Haematology, Royal Free Hospital School of Medicine, London, England; A. V. Hoffbrand, Department of Haematology, Royal Free Hospital School of Medicine, London, England; M. Hoffman, Long Island Jewish Medical Center, Division of Hematology/Oncology, New Hyde Park, New York, USA; G. Juliusson, Division of Clinical Hematology and Oncology, Department of Medicine, Karolinska Institute, Huddinge Hospital, Huddinge, Sweden; G. Konwalinka, Department of Internal Medicine, University of Innsbruck, Innsbruck, Austria; J. Liliemark, Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden; R.A. Nagourney, Experimental Therapeutics, Memorial Cancer Institute, Long Beach, California, USA; M. Shimoyama, Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.