Leukemia & Lymphoma, June 2011; 52(S2): 29–33
Development of cladribine at Scripps for hairy cell leukemia and current results
MELISSA L. TORREY1, DARREN S. SIGAL1, & ALAN SAVEN1,2
1Division of Hematology/Oncology, Scripps Clinic, La Jolla, CA, USA and 2J. Dallas Clark Chair in Clinical Cancer Research, Ida M. and Cecil H. Green Cancer Center, La Jolla, CA, USA
Abstract Hairy cell leukemia (HCL) is an indolent, mature B-cell lymphoproliferative malignancy that clinically manifests as pancytopenia and fibrosis of the bone marrow, ultimately leading to recurrent infections and splenomegaly. This article reviews the extensive experience at Scripps Clinic with cladribine (2-chlorodeoxyadenosine; 2-CdA) in HCL. It is currently recommended as first-line treatment in HCL, because of its proven efficacy with associated low toxicity profile and brevity of treatment duration, with the majority of responses being complete (CRs). This was achieved after only a single 7-day infusion. We also discuss the success of cladribine in patients with relapsed and refractory HCL and potential approaches to eradicating minimal residual disease (MRD). MRD is thought to predict for future relapses. The eradication of MRD warrants continued study in order to further improve disease-free survival, which may translate into ultimately curing patients with HCL.
Keywords: Cladribine, hairy cell leukemia
Introduction Purine nucleoside analogs have replaced splenect- omy and interferon-a (IFN-a) as standard front-line therapy in hairy cell leukemia (HCL). Pentostatin (2- deoxycoformycin) and cladribine (20-chlorodeoxya- denosine) both induce durable complete responses (CRs) in the majority of both untreated and previously treated patients with HCL [1]. Although comparative data are lacking, cross-study analyses demonstrate that cladribine and pentostatin both achieve high overall response (ORR; 98% and 96%, respectively) and CR (91% and 81%, respectively) rates, with protracted response intervals [2,3]. Based on the impressive activity of both agents, cladribine has emerged as the standard front-line drug in HCL therapy. We review the pivotal studies conducted at Scripps Clinic that preferentially support the front- line use of cladribine as an extremely active, well tolerated agent that induces very prolonged remis- sions. We also evaluate the importance of minimal residual disease (MRD) in HCL [4].
Mechanism of action of cladribine
Cladribine is a purine nucleoside analog that is cytotoxic to both actively dividing and resting cells. Cladribine is taken into cells via an active transport mechanism. Upon intracellular entry, deoxycytidine kinase (DCK) serially phosphorylates cladribine to its nucleoside triphosphate. The chlorine substitution at the 2 position of the purine ring prevents its catabolism by adenosine deaminase. The accumula- tion of cladribine triphosphate produces cellular cytotoxicity by direct DNA effects and alterations in the mitochondrial membrane. Constitutive activity of DCK in lymphocytes renders them exquisitely sensitive to cladribine. Figure 1 illustrates the mechanism of action of cladribine in both resting and dividing lymphocytes.
Development and dosing of cladribine
The development of cladribine came through an enhanced understanding of the pediatric disorder,
Correspondence: Alan Saven, MD, Head, Division of Hematology/Oncology, MS 217, Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA 92037, USA. Tel: (858)554-8388. Fax: (858)554-6941. E-mail:
saven.alan@
scrippshealth.org
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.569621
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