30
M. L. Torrey et al.
Figure 1. Mechanism of action of cladribine.
severe combined immunodeficiency disease (SCID), in which lymphocytopenia ensues because of adeno- sine deaminase (ADA) deficiency. Dennis Carson hypothesized that an ADA-resistant purine analog would kill lymphocytes [5]. Cladribine, or 2-chlor- odeoxyadneosine, was then selected as the most potent for clinical development. Investigators at Scripps Clinic, under the direction of Ernest Beutler, then applied cladribine to the treatment of lymphoid hematologic malignancies, including HCL [6]. The initial phase I study of cladribine conducted at
Scripps Clinic determined the most efficacious and safe dose of cladribine to be 0.1 mg/kg per day, delivered as a 7-day continuous infusion. Although alternative dosing schedules have been studied, we continue to favor our initial approach.
Pivotal results with cladribine at Scripps Clinic
Piro and colleagues at Scripps Clinic first reported on 12 patients with HCL who were administered cladribine at the standard dose of 0.1 mg/kg per day as a 7-day continuous infusion [7]. Eleven of the 12 patients achieved a CR and one patient had a partial response (PR), with a reduction in spleen size and a 50% decrease in marrow involvement. Patients who achieved CR experienced a rapid decline in the number of circulating hairy cells. Normalization of the hemoglobin, neutrophil count, and platelet count typically occurred within 8 weeks of receiving cladribine [7]. Saven and colleagues built on the initial Scripps Clinic, La Jolla, California, cohort, expanding the number of cladribine-treated patients with HCL to 349, constituting the largest single-
Table I. Responses to cladribine in the front-line setting. No.
Investigators
Saven et al. [2]
Estey et al. [14]
Juliusson & Liliemark [15]
Hoffman et al. [16]
Tallman et al. [17]
Dearden et al. [9]
Total
of patients CRs 349
319
46 16
49
50 45
555
36 12
37
40 38
PRs 22
5 0
12
9 7
Minor/no response
8
5 4
0
1 0
482 (87%) 55 (10%) 18 (3%)
institution database of patients with HCL. Overall, 319 (91%) patients achieved CRs and 22 (7%) had PRs, with a 52-month median duration of response [2]. The overall survival (OS) rate was 96% at 48 months [3] (Table I). Extended follow-up, beyond 7 years, of 209 patients with HCL from the Scripps Clinic cohort noted 97% OS at 108 months. These results documented that cladribine’s significant ac- tivity is also long-lasting by producing very durable remissions. Also, patients who experienced relapse could successfully be re-treated with cladribine (see further in ‘Relapses after prior therapy with cladri- bine’ below) [8]. Cross-study comparisons with pentostatin revealed two effective agents that could produce durable responses, but cladribine was also very well tolerated and only required a single 7-day
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