40 (10

229 (55

26 (6

121 (29

percent) percent) percent) percent)

percent) percent) percent) percent)

and CD54, leukocyte adhesion molecules, which is accompanied by enhanced susceptibility to lysis by cytotoxic T lymphocytes.74

The standard dose recommendation for alpha-2b interferon therapy is 2 million units/m2, administered subcutaneously three times per week for 12 months, and that for alpha-2a interferon is 3 million units subcutaneously daily for 6 months and then decreased to three times per week for an additional 6 months.

Purine Nucleoside Analogues

In 1972 Giblett et al. made the seminal observation that one-third of children with severe combined immunodeficiency syndrome (SCID) were deficient in the purine catabolic enzyme adenosine deaminase.75 Adenosine deaminase catalyzes the irreversible deamination of adenosine to inosine and of 2'-deoxyadenosine to 2'-deoxyinosine. Cohen and associates reported that the intracellular accumulation of deoxyadenosine triphosphate was responsible for this lymphopenia.76 Later, Carson et al. found 2-chlorodeoxyadenosine, a chlorine-substituted purine deoxynucleoside, to be the most potent among a panel of substituted purine analogues screened for in vitro tox-icity toward an L1210 murine leukemia.77 This enhanced insight into the biochemical pathways of adenosine metabolism provided the rational basis for the clinical development of the three newer purine analogues that mimic this experiment of nature. 2'-Deoxycoformycin (dCF) irreversibly binds to adeno-sine deaminase, and fludarabine and 2-chlorodeoxyadenosine (2-CdA) resist deamination in the purine salvage pathway. 2'-Deoxycoformycin and 2-chlorodeoxyadenosine have been demonstrated to have major activity in a variety of indolent lymphoid malignancies, but their action is most profound in the treatment of HCL. Fludarabine, although more fully evaluated in other lymphoproliferative disorders, has been administered to only a few patients with HCL.

2'-Deoxycoformycin 2'-Deoxycoformycin (dCF, Pentostatin, Nipent; SuperGen, Pleasanton, CA) is a natural product isolated from the cultured broth of Streptomyces antibioticus. In 1983 dCF was first shown to have activity in a single patient with HCL.78 The successful administration of low-dose dCF, 5 mg/m2 for 2 to 3 days, then weekly for 15 to 16 doses, was reported in 1984.79

The Eastern Cooperative Oncology Group (ECOG) treated patients with dCF administered at 5 mg/m2 for 2 days every other week until complete remission was achieved.80 Of 27 evaluable patients with HCL, there were 16 (59 percent) complete responders, 10 (37 percent) partial responders, and 1 non-responder. When this study was updated with 50 patients accrued, 32 (64 percent) of patients achieved a complete remission and 10 (20 percent) of patients a partial remission.80

The encouraging high overall response rates and complete remissions seen with dCF prompted the National Cancer Institute to organize a prospective, randomized, intergroup study of dCF versus interferon alfa-2a in previously untreated HCL patients.81 Patients were randomized to either interferon alpha-2a at 3 million units subcutaneously three times per week or dCF at 4 mg/m2

intravenously every 2 weeks. Patients who did not respond after 6 months to initial treatment were crossed over. Among interferon patients, 17 of 159 (11 percent) achieved a complete response and 60 of 159 (38 percent) had either a complete or partial response. Among dCF patients, 121 of 154 (79 percent) achieved responses, of which 117 (76 percent) were complete. Of patients who progressed on interferon and who were then treated with dCF, 66 percent achieved a complete response and 9 percent a partial response. No patients who had progressed on dCF responded to interferon. The difference in overall survival between the two groups was not statistically significant, which likely reflects the crossover study design. These results indicate that dCF is substantially more active than interferon when administered as first-line therapy to patients with HCL.

2 '-Deoxycoformycin-induced toxicities include fever, nausea, vomiting, photosensitivity, and keratoconjunctivitis.79,82 Severe myelosuppression may occur soon after the initiation of dCF therapy, especially in those patients with preexisting marrow compromise.80,83 Patients with satisfactory pretreatment hematologic parameters tend to have less myelosuppression following dCF administration. Serious infections, including disseminated herpes zoster, Escherichia coli, Haemophilus influenzae, pneumococcal, and fungal infections (fatal in some patients), were observed early on following the initiation of dCF.82 In patients with active and uncontrolled infections, a poor performance status, or impaired renal function, dCF is best avoided.84 2 '-Deoxycoformycin is a potently immunosuppressive agent.85 During dCF therapy and for at least 14 months following its administration, CD4 and CD8 lymphocytes may decrease to levels below 200 cells per microliter. Low doses of dCF also cause severe immunosuppression.86 CD4 cells were reduced from a pretreatment median of 669 per microliter to a posttreatment median of 155 per microliter. Despite the severity and duration of the immunosuppression, no significantly increased frequency of either late opportunistic infections or secondary malignancies has been reported thus far. This risk will be clarified with longer follow-up times and larger numbers of patients.

When the results of six studies are combined, the overall response rate is 86 percent, of which 72 percent are complete and 14 percent partial responses (Table 8-5). The standard dose of dCF for patients with HCL is 4 mg per square meter of body surface area every other week for 3 to 6 months until maximum response is obtained.

2-Chlorodeoxyadenosine 2-Chlorodeoxyadenosine (2-CdA, Cladribine, Leustatin; OrthoBiotech, Raritan, NJ) is the chlorinated derivative of 2 -deoxyadenosine and is phosphorylated to its putative active form by deoxycytidine kinase. It is unique among other more conventional antimetabolites in that it is toxic to both dividing and resting lymphocytes, which likely accounts for its major activity in the treatment of indolent lym-phoproliferative disorders.87,88

In 1990 investigators from Scripps Clinic reported on 12 HCL patients treated with a single 7-day course of 2-CdA at 0.1 mg/kg/day by continuous intravenous infusion.89 Of those 12 patients, 11 achieved a complete response and 1 a partial response. In 1998 Saven et al. reported the long-term follow-up

Table 8-5. 2'-Deoxycoformycin (dCF), 2-Chlorodeoxyadenosine (2-CdA), and Fludarabine Treatment in Hairy Cell Leukemia

Response (percent)

Table 8-5. 2'-Deoxycoformycin (dCF), 2-Chlorodeoxyadenosine (2-CdA), and Fludarabine Treatment in Hairy Cell Leukemia

Response (percent)







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