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F/U

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

Carrera3 Scripps Clinic 1990 12 92% 8% 100% 0 16 months

Carrera3 Scripps Clinic 1990 12 92% 8% 100% 0 16 months et al. reported in 1997 on 49 patients with hairy cell leukemia treated at Long Island Jewish Medical Center, with a single 7-day continuous infusion of 2-CdA.9 They reported a 76% CR rate and a 24% PR rate. At 55-months median follow-up, there was an 80% relapse-free survival rate and a 95% overall survival rate.

In the largest study on the use of 2-CdA to treat hairy cell leukemia, Cheson et al. reported in 1998 on 979 patients treated through the Group C protocol mechanism at the National Cancer Institute.10 Of 861 evaluable patients, a CR was obtained in 50% and a PR in 37%. The relapse rate at a median follow-up of 52 months was 12%. Although the CR in this study, which the authors felt approximated general clinical practice to a greater degree than single-institution studies, was lower, this may have been related to the lack of central pathology review.

Finally, in a British study published in 1999, Dearden et al. from the Royal Marsden Hospital in London described their long-term results with both pentostatin and cladribine in patients with hairy cell leukemia.11 Forty-five patients were treated with cladribine, with 84% achieving a CR, and a 16% PR rate was observed. At 45 months, the relapse rate was 29%.

Despite the durability of the responses generated by cladribine, it is clear that a proportion of patients in apparent CR without morphologic evidence of residual disease in the bone marrow actually have demonstrable disease when more sensitive tests to detect minimal residual disease are used. In a study reported by Hakimian et al. from Northwestern University, 5 of their 24 patients in apparent CR 3 months after treatment with 2-CdA had residual disease when paraffin blocks of their bone marrows were stained with anti-CD20 and anti-CD45Ro antibodies.12 In a separate investigation, 154 complete remission bone marrow biopsies from HCL patients treated with 2-CdA at Scripps Clinic were analyzed with anti-CD20 and DBA.44 immunostains.13 Overall, 50% of the biopsies exhibited staining with anti-CD20 and/or DBA.44 in hairy cells, indicating residual disease. However, in those patients with immunophenotypic minimal residual disease and normal peripheral blood counts, there was no documented increase in the number of marrow hairy cells on serial bone marrow evaluation. So, although it is clear that a significant proportion of patients in morphologic CR actually harbor minimal residual disease, the clinical significance of this finding remains unclear.

In summary, a single course of cladribine given as a 7-day continuous intravenous infusion induces a complete remission in a high proportion of patients who meet the indications for therapy. The ORR approaches 100%. With extended follow-up, the responses achieved are durable, and the majority of patients with relapsed disease achieve further responses with retreatment. However, even with extended follow-up, there is no clear plateau on the time to treatment failure curve, and it remains to be seen to what extent 2-CdA represents curative therapy.

Alternate methods of administration

A variety of different 2-CdA routes and schedules of administration have been investigated in an attempt to reproduce the high response rates seen with the 7-day continuous infusion schedule while also decreasing the associated myelosuppression and improving convenience of administration. On the basis of their earlier pharmacokinetic studies revealing a terminal half-life of 7-10 h for 2-CdA, Juliusson et al. reported in 1995 on their experience in hairy cell leukemia with daily subcutaneous injections of 2-CdA for seven consecutive days.14 They documented a CR rate of 81% in their 73 patients, similar to the excellent rates achieved with continuous intravenous infusion. In addition, they did not observe significant injection site reactions.

Lauria et al. treated 25 hairy cell leukemia patients who had severe cytopenias (ANC <1.0 X 109/L prior to therapy) with a regimen of weekly 2-CdA, dosed at 0.15 mg/kg intravenously for 6 weeks.15 They observed a CR in 76% of their patients, a PR in 24%, and only a 16% incidence of severe neutropenia (ANC <0.5 X 109/L). The median duration of response in these 19 patients, however, was only 15 months. Liliemark et al. studied the feasibility of delivering 2-CdA by the oral route.16 In 13 patients with B-cell chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL), they delivered intravenous, subcutaneous, and oral preparations of 2-CdA (either in liquid or capsule form) in an alternating fashion. On the basis of pharmacokinetic data, they concluded that an AUC resembling that of a 2-h intravenous infusion could be obtained with an oral preparation at double the dose.

There have been additional investigations using 2-CdA delivered as a 2-h intravenous infusion in other low-grade lymphoproliferative disorders, including CLL, NHL, and lymphoplasmacytic lymphoma. These investigations have all documented equivalent feasibility and tolerability. However, there have not been any comparative studies of 2-CdA demonstrating a superiority of any alternate mode of delivery over the traditional 7-day continuous intravenous infusion in hairy cell leukemia. Because of the excellent long-term efficacy and safety data using this route and schedule, 0.1 mg/kg of 2-CdA delivered by continuous intravenous infusion daily for 7 days remains the regimen of choice.

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