Relative to traditional antimetabolites, 2CDA is unique in that it is equally active against dividing and resting lymphocytes, which is essential for the observed activity of 2CDA in indolent lymphoproliferative disorders. However, 2CDA has also shown significant activity in certain solid tumors and autoimmune conditions.
Of the lymphoproliferative conditions that have been treated with 2CDA, hairy cell leukemia (HCL) has shown the most dramatic response. It is administered over a 7-day period by intravenous infusion at a dose of 0.09 mg/kg. Overall response rates in clinical studies have ranged from 80% to 100%, with a large majority of these being complete remissions. 2CDA is approved by the U.S. FDA for the treatment of active HCL and is indicated for symptomatic patients, those with significant neutropenia, leukocytosis, anemia, thrombocytopenia, splenomegaly, constitutional symptoms due to HCL, recurrent serious infections, and painful lymphadenopathy. A review of the guidelines for clinical use of 2CDA in HCL has recently appeared (Goodman et al., 2003). 2CDA also has activity in CLL (Juliusson et al., 1992; Saven, 1995), non-Hodgkin lymphoma (Kay et al., 1992; Hickish et al., 1993), Waldenstrom macroglobulinemia (Dimopoulos et al., 1993), cutaneous T-cell lymphoma (Saven et al., 1992), acute myelogenous leukemia (AML) (Carson et al., 1984; Santana et al., 1992), and chronic myelogenous leukemia (CML) (Beutler, 1993; Saven et al., 1994).
A particularly difficult-to-treat lymphoproliferative disorder is CLL, a disease caused by the proliferation and accumulation of B lymphocytes. It is the most common form of leukemia in North America and Europe. The alkylating agent chlorambucil, with or without prednisone, is the standard initial treatment (Foon et al., 1990). 2CDA has also been used as initial therapy for CLL patients. Patients who received purine nucleoside analogues, such as 2CDA or fludarabine, as their initial therapy and achieved long-lasting response can be successfully retreated with the same agent. Purine nucleoside analogues administered in combination with other chemotherapeutic agents and/or monoclonal antibodies may produce higher response rates, including complete response, compared with purine nucleoside analogs alone or other treatment regimens (Robak, 2005a,b). A study of the activity of 2CDA was conducted in 90 CLL patients, mostly Binet stage C disease who had failed alkylator therapy, and resulted in 4% complete responses and 40% partial responses (Saven, 1996). Here, the ratio of dCK to cytoplasmic 5'-nucleotidase was predictive of 2CDA responsiveness (Kawasaki et al., 1993). In combination studies in fludarabine-resistant CLL patients, pretreatment with bryostatin 1 has been shown to potentiate the efficacy of 2CDA by increasing the ratio of dCK to 5'-nucleotidase activity (Ahmad et al., 2000; Beck et al., 2004). However, a study in 20 previously untreated CLL patients who were administered 2CDA as a 7-day continuous infusion for four courses achieved 25% complete responses and 60% partial responses for an overall response rate of 85% (Saven et al., 1995). In another study, oral 2CDA was evaluated in 126 previously untreated CLL patients and compared with 40 previously treated patients (Karlsson et al., 2002). The overall responses were 77% and 39% in these groups, respectively. Interestingly, in these studies the achievement of complete remission was not a prerequisite for long-term survival. Combination preclinical and clinical studies using 2CDA with other cytotoxic agents and/or monoclonal antibodies show synergistic actions (Robak et al., 2005a,b). These and other studies establish the significant activity of 2CDA, used alone or in combination with other agents, in patients with previously treated and untreated CLL (Robak, 2005a,b).
Patients with low-grade non-Hodgkin lymphoma have been responsive to 2CDA as a single agent (Kay et al., 1992; Hickish et al., 1993) and in combination with mitoxantrone (Saven et al., 1996; Rummel et al., 2002) or cyclophosphamide (Van Den Neste et al., 2000; Robak et al., 2001). 2CDA is also active in advanced, untreated low-grade lymphomas, but myelosuppression is a cumulative adverse effect and limits the number of courses of treatment that can be given (Canfield et al., 1997).
In a study of 15 patients with cutaneous T-cell lymphoma treated with 2CDA after having failed standard topical and/or systemic therapy, the overall response rate was 47%. Three of 15 patients (20%) achieved complete responses, and four of 15 patients (27%) achieved partial responses (Saven et al., 1992). The median duration of response was 5 months.
Several studies conducted with 2CDA as a single agent in patients with Waldenstrom macroglobulinemia, a B-cell neoplastic condition, showed good overall response rates from 55% to 100%, with the higher response rates noted in the previously untreated patient groups (Dimopoulos et al., 1993; O'Brien et al., 1996; Fridrik et al., 1997; Liu et al., 1998).
Modest activity has been seen with 2CDA in myeloid leukemias. In CML, one study showed an overall response rate of 47% in patients previously treated with combination therapies (Dann et al., 1998). In another study, 2CDA was also active in chronic-phase CML, inducing complete hematologic responses in these patients, but the absence of cytogenetic responses and severe immunosuppression limit its clinical use (Saven et al., 1994). In AML, 2CDA has single-drug activity and may enhance the formation of the active metabolite (ara-CTP) of cytosine arabinoside (ara-C) in combination (Juliusson et al., 2003). In fact, this combination along with idarubicin showed an overall complete response rate of 62% with 30% long-term survival (>2 years). In relapsed/refractory AML, however, 2CDA is ineffective (Gordon et al., 2000). The mechanism of activity in myeloid leukemias is unclear since only low levels of dCK are expressed in granulocytes (Carson et al., 1980, 1983).
In other studies, 2CDA was devoid of activity in patients with multiple myeloma (Dimopoulos et al., 1992) but has shown promise in the treatment of Langerhans histiocytosis (Dimopoulos et al., 1997) and B-cell prolymphocytic leukemia, inducing high overall and complete response rates (Saven et al., 1997).
Because 2CDA and other similar purine nucleoside analogs are active antimetabolites in both proliferating and resting lymphoid cells, it was thought that these agents might have significant activity against certain solid tumors as well. A dose-escalation study of 2CDA in patients with various solid tumors was conducted to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses (Saven et al., 1993). In these studies, two of seven patients (28.6%) with malignant astrocytomas obtained partial responses with a median duration of 8 months. Interestingly, there was no clinical correlation with dCK expression and response to 2-CdA. Another phase 1 clinical trial was conducted to determine the MTD in 18 patients with solid tumors (non-small-cell lung and colorectal) given 2CDA by 1-hour intermittent infusion, repeated daily for 5 days. No responses were observed (Kobayashi et al., 1994). There is some in vitro evidence that 2CDA could be useful against hepatocellular carcinomas (Graziadei et al., 1998), but no clinical trials for this solid tumor type have been reported. With limited exceptions, 2CDA as a single agent has not shown significant activity in solid tumors.
16.4.3 Multiple Sclerosis and Other Nonmalignant
It is not surprising, given the antilymphocyte activity of 2CDA, that the use of this agent to suppress an inappropriate immune response has been investigated. Multiple sclerosis (MS) is characterized by clinical signs and symptoms of CNS demyelina-tion. The disease can be chronic and progressive and have relapsing and remitting stages. Although MS is thought to be a lymphocyte-dependent autoimmune disease, the specific antigens and triggering agents involved in the disease are unknown. The rationale for the use of 2CDA in MS is that autoantigen-specific T-lymphocytes are thought to be activated peripherally before migrating to the CNS, where they mediate damage to myelin (Hafler and Weiner, 1989). This suggests that 2CDA-induced reduction in the number of lymphocytes may help slow the progression of the disease. The use of 2CDA in MS has been studied, and its potential use in this disease has been reviewed (Langtry and Lamb, 1998). In a 2-year placebo-controlled, doubleblind, crossover study to evaluate 2CDA in the treatment of chronic progressive multiple sclerosis, analysis of the results revealed a favorable influence on the neurological performance scores in both the Kurtze extended disability status and the Scripps neurological rating scale and also on MRI findings in patients treated with 2CDA. In the first year, the most striking finding was that while clinical deterioration continued in the placebo-treated patients, the condition of patients who received 2CDA stabilized or even improved slightly (Beutler et al., 1996). In another study, a double-blind, placebo-controlled, randomized trial of 2CDA in relapsing-remitting MS was conducted in which 2CDA given by subcutaneous injection had a favorable effect on the frequency and severity of relapses and MRI findings. MRI-enhancing lesions were completely suppressed in the 2CDA patients by the sixth month of treatment (Romine et al., 1999). Thus, 2CDA has shown promise in the treatment of both progressive and relapsing-remitting MS.
In addition to MS, other nonmalignant disorders have responded to 2CDA treatment (Beutler et al., 1997a,b). Among them, autoimmune hemolytic anemia seems to respond to 2CDA in some patients but may be induced in others, usually in those with concomitant CLL after several courses of treatment (Robak et al., 1997), but has also been reported in some patients with Waldenstrom macroglobulinemia (Tetreault and Saven, 2000). The finding that human monocytes were as sensitive to 2CDA toxicity as lymphoid cells suggested that these analogs could offer a novel therapeutic strategy for chronic inflammatory and autoimmune diseases characterized by inappropriate monocyte deployment or function (Carrera et al., 1990). Rheumatoid arthritis (RA) and inflammatory bowel disease are two inflammatory diseases for which 2CDA therapy has shown some efficacy, although 2CDA is clearly not an anti-inflammatory agent. Combined analysis of three studies involving 23 patients with longstanding RA who were given either continuous or 4-hour infusions, or were given oral 2CDA, indicated that more than half of the patients had >20% improvement in joint swelling during 2CDA treatment (Beutler et al., 1997a,b). The effect of the drug on pain and tenderness was less dramatic. Collectively, these data support the hypothesis that 2CDA may retard the pannus formation in patients with longstanding RA. Whether or not 2CDA can decrease joint erosions in RA patients remains to be established.
Primary sclerosing cholangitis (PSC) is a chronic hepatic autoimmune disorder of unknown etiology, thought to be mediated by biliary autoreactive cytotoxic lymphocytes. A study was conducted in four patients with stages I and II PSC who were given 2CDA subcutaneously in an open-label pilot trial of 6-month duration and 2-year followup (Duchini et al., 2000). Patients had a quantifiable decrease in the hepatic inflammatory infiltrate on liver biopsy. No significant changes were found in symptom scores, liver panel tests, or cholangiograms. However, the drug was well-tolerated, and two of four patients reported remission of their inflammatory bowel disease symptoms.
Psoriasis and psoriatic arthritis are conditions for which an immune pathogen-esis is indicated by the association of the disease with particular HLA types, by the dense lymphocyte infiltrates seen in both the skin and affected joints, and by beneficial effects of treatment with cyclosporine A and anti-CD4 antibodies (Bos et al., 1989). A study of 2CDA given orally to six patients weekly for 12 weeks followed by monthly maintenance therapy showed that after 6 months, four out of six patients had improved joint disease, and five out of six had improved psoriasis (Eibschutz et al., 1995).
Finally, because the only toxicity of 2CDA noted in the early studies was bone-marrow suppression, it has been used in preparing patients with lymphomas and leukemias for bone-marrow transplantation because destruction of the marrow in such patients is a part of the therapeutic aim (Beutler et al., 1997a,b).
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