Figure 31.1 (a) Normal pathway for deoxynucleotide metabolism and the mechanism of action of 2'-deoxycoformycin (pentostatin). Deoxyadenosine is normally converted to deoxyinosine through the action of adenosine deaminase. In the congenital absence of adenosine deaminase (such as in severe combined immunodeficiency), or in the presence of DCF, a potent direct inhibitor of adenosine deaminase, deoxyadenosine triphosphate accumulates because of the high ratio of deoxycytidine kinase (dCK) relative to 5'-nucleotidase (5'-NT). This accumulation of deoxyadenosine triphosphate results in cell death. (b) Mechanism of action of 2-chlorodeoxyadenosine (cladribine). 2-CdA enters the cell through an efficient transport system. It is resistant to the action of adenosine deaminase. Because of the high ratio of deoxycytidine kinase to 5'-nucleotidase in lymphocytes, 2-chlorodeoxyadenosine triphosphate accumulates and results in DNA strand breaks, leading to cell death

(PR); on follow-up, none of the patients had relapsed, with a 15.5-month median remission duration.4

These encouraging results led to further investigations, and in 1998, Saven et al. published the long-term follow-up of 358 patients treated with a single course of continuous intravenous infusion of 2-CdA for 7 days.5 Ninety-one percent of their 349 evaluable patients achieved a CR, with resolution of peripheral cytopenias (i.e., ANC >1.5x109/L, hemoglobin >12 g/dL, and platelets >100x109/L), no evidence of hairy cells morphologically in the bone marrow, and resolution of all adenopathy and splenomegaly. Seven percent of the patients achieved a PR, for an overall response rate (ORR) of 98%. Twenty-six percent of these patients relapsed at a median of 29 months from therapy. An additional CR was achieved in 62% of the relapsed patients who were treated with a second course of 2-CdA; 26% of these retreated patients achieved a PR. The treatment failure rate at 48 months was 18.7% with a 96% overall survival at 48 months.

Goodman et al. reported in 2003 on the extended follow-up of these patients treated at Scripps Clinic.6 Of the 209 patients treated at that institution with at least 7 years of follow-up, there was a 95% CR rate and a 5% PR rate. The median response duration was 98 months.

Of the 37% experiencing a relapse, the median time to relapse was 42 months. Of these relapsed patients treated with a second course of 2-CdA, 75% achieved a CR and 17% a PR. The overall survival at 108 months was 97%.

These excellent response rates and response durations with the use of a single infusion of cladribine have been confirmed in other single-institution series (see Table 31.1). In 1992, Estey et al. reported on 46 patients with hairy cell leukemia treated at MD Anderson Cancer Center, Houston, TX.7 They delivered the 2-CdA by continuous intravenous infusion at a dose of 40 mg/m2 per day for 7 days; the CR rate was 78% and the PR rate was 11%. Only one patient relapse was observed in the group of responding patients, but follow-up was limited at 37 weeks.

In 1996, Tallman et al. described the experience at Northwestern University in 52 consecutive patients with a 2-CdA treatment protocol of 0.1 mg/kg per day, by continuous intravenous infusion for 7 days.8 They observed an 80% CR rate with an 18% PR rate. Fourteen percent of the patients relapsed at a median of 24 months. Of five patients retreated with a second course of 2-CdA, two patients achieved a CR and three a PR. The overall survival at 4 years was 86%. Hoffman

Saven5 Scripps Clinic 1998 349 91% 7% 98% 18.7% 48 months

Goodman3,6 Scripps Clinic 2003 207 95% 5% 100% 37% >84 months

Estey7 MDACCc 1992 46 78% 11% 89% 2.4% 37 weeks

Tallman8 Northwestern 1996 52 80% 18% 98% 28% 48 months

Hoffman9 LI Jewishd 1997 49 76% 24% 100% 20% 55 months

Cheson10 NCIe 1998 861 50% 37% 87% 12% 52 months

Dearden11 Royal Marsdenf 1999 45 84% 16% 100% 29% 45 months a Study reports on the subset of patients previously reported by Saven et al.5 with more than 7 years of follow-up. b Relapse is reported within the follow-up period listed. c MD Anderson Cancer Center, Houston, TX. d Long Island Jewish, New York. e National Cancer Institute. f Royal Marsden Hospital, London, England

Table 31.

1 Trial results of 2-CdA in hairy cell leukemia

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