2-Chlorodeoxyadenosine: A Newer Purine Analog Active in the Treatment of Indolent Lymphoid Malignancies

  1. Alan Saven, MD; and
  2. Lawrence D. Piro, MD
  1. From the Ida M. and Cecil H. Green Cancer Center, Scripps Clinic and Research Foundation, La Jolla, California. Requests for Reprints: Alan Saven, MD, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037.
     
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    Abstract

    Objective: To review the structure, mechanism of action, pharmacologic features, and clinical trial results of the newer purine analog, 2-chlorodeoxyadenosine (2-CdA).

    Data Sources and Study Selection: English-language medical literature review of more than 70 articles.

    Data Synthesis: 2-Chlorodeoxyadenosine is unique compared with traditional antimetabolite drugs in that it is equally active against dividing and resting lymphocytes, which may be especially important in indolent lymphoid malignancies, such as chronic lymphocytic leukemia, because most cells in these disorders are in the resting phase. In patients with alkylator-refractory chronic lymphocytic leukemia who were treated with 2-CdA, 44% achieved a response (4% complete responses, 40% partial responses), and 54%, scored as nonresponders, had a sustained reduction in their peripheral lymphocytosis. Patients with untreated chronic lymphocytic leukemia had an 85% response rate (25% complete responses, 60% partial responses). Patients with previously treated low-grade lymphoma achieved an overall response rate of 43%. The most striking clinical effects of this drug have been seen in hairy cell leukemia, in which a single course of therapy induces complete remissions in 85% of partial remissions in 12%. Activity has also been shown in cutaneous T-cell lymphoma and the myeloid leukemias.

    Conclusions: 2-Chlorodeoxyadenosine is a newer purine analog with potent activity in the treatment of indolent lymphoproliferative diseases and illustrates the model for rational drug development.

    2-Chlorodeoxyadenosine ([2-CdA], cladribine; Leustatin, Ortho Biotech, Raritan, New Jersey), along with fludarabine [1] and 2′-deoxycoformycin [2], is a newer purine analog with major activity in the treatment of indolent lymphoid malignancies. Fludarabine (Fludara, Berlex Laboratories, Alameda, California) is approved by the Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia who are refractory to alkylating agents [3], 2′-deoxycoformycin (Nipent, Parke Davis; Morris Plains, New Jersey) for the treatment of interferon-refractory hairy cell leukemia, and 2-CdA for patients with untreated or interferon-refractory hairy cell leukemia.

    The development of 2-CdA emerged from an improved understanding of the mechanisms of lymphopenia in adenosine deaminase-deficient children with severe combined immunodeficiency disease. We review the development, structure, mechanism of action, pharmacologic features, and the clinical trial results of this important new chemotherapeutic agent.

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    Lessons from Adenosine Deaminase Deficiency

    In 1972, Giblett and colleagues [4] made the serendipitous but seminal observation that some infants with severe combined immunodeficiency disease were adenosine deaminase deficient. Cohen and colleagues [5] later established the relation between the intracellular accumulation of deoxyribonucleotides (resulting from adenosine deaminase deficiency) and lymphocytotoxicity. Carson and colleagues [6] evaluated a panel of purine deoxynucleosides synthesized to be resistant to deamination by adenosine deaminase for toxicity in vitro and identified 2-CdA as the most potent. 2-Chlorodeoxyadenosine induces a lymphopenic state, similar to that seen in adenosine deaminase deficiency, by resisting deamination and thereby accumulating in its triphosphate form with resultant lymphocytotoxicity.

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    Structure and Synthesis

    2-Chlorodeoxyadenosine is a deoxyadenosine analog, consisting of substitution of a chlorine atom for the hydrogen atom at the 2-position of the purine ring (Figure 1). It was first synthesized by Christensen and colleagues [7], using direct fusion alkylation of 2,6-dichloropurine. Later, Carson and colleagues [6] synthesized 2-CdA from 2-chloroadenine and thymidine using a transdeoxyribosylase from Lactobacillus helveticus. The drug in commercial use today is synthesized nonenzymatically using a sodium salt glycosylation procedure.

    Figure 1.
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    Figure 1. Molecular structures of deoxyadenosine and 2-chlorodeoxyadenosine.
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    Mechanisms of Action

    Adenosine deaminase catalyzes the irreversible deamination of deoxyadenosine to deoxyinosine (Figure 2). Deoxycytidine kinase phosphorylates purine deoxyribonucleotides, whereas 5′-nucleotidase dephosphorylates them. Lymphocytes have high deoxycytidine kinase to 5′-nucleotidase ratios, favoring triphosphate formation [8] and making them ideal target cells for 2-CdA.

    Figure 2. Deoxyadenosine ( ) enters the cell through an efficient transport system. The favorable ratio of deoxycytidine kinase ( ) to 5′-nucleotidase (5′- ) results in the formation of deoxyadenosine monophosphate ( ), -diphosphate ( ), and -triphosphate ( ). Adenosine deaminase ( ) irreversibly deaminates deoxyadenosine ( ) to deoxyinosine ( ). Purine nucleoside phosphorylase ( ) catalyzes the reversible phosphorolysis of deoxyinosine to hypoxanthine, which is oxidized by xanthine oxidase ( ) to uric acid to be excreted.
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    Figure 2. Deoxyadenosine ( ) enters the cell through an efficient transport system. The favorable ratio of deoxycytidine kinase ( ) to 5′-nucleotidase (5′- ) results in the formation of deoxyadenosine monophosphate ( ), -diphosphate ( ), and -triphosphate ( ). Adenosine deaminase ( ) irreversibly deaminates deoxyadenosine ( ) to deoxyinosine ( ). Purine nucleoside phosphorylase ( ) catalyzes the reversible phosphorolysis of deoxyinosine to hypoxanthine, which is oxidized by xanthine oxidase ( ) to uric acid to be excreted. Deoxyadenosine metabolism.d. adenosineDCKNTd. AMPd. ADPd. ATPADAd. adenosined. inosinePNPXO

    2-Chlorodeoxyadenosine enters the cell through an efficient transport system and is phosphorylated by deoxycytidine kinase. 2-Chlorodeoxyadenosine triphosphate is a potent inhibitor of ribonucleotide reductase and DNA polymerase-α (Figure 3). 2-Chlorodeoxyadenosine triphosphate accumulation also depletes the intracellular pool of deoxynucleotides [9]. In actively dividing cells, DNA synthesis is then impaired by the preferential use of 2-chlorodeoxyadenosine triphosphate by DNA polymerase and the retardation of DNA chain elongation [10].

    Figure 3. 2-Chlorodeoxyadenosine ( ) enters the cell through an efficient transport system where it resists (‡) deamination by adenosine deaminase ( ). The high ratio of deoxycytidine kinase ( ) to 5′-nucleotidase ( ) favors the formation of 2-chlorodeoxyadenosine monophosphate ( ), -diphosphate ( ), and -triphosphate ( ). In dividing cells, excess 2-CdATP inhibits ribonucleotide reductase ( ) with resultant inhibition of DNA synthesis. In resting cells, DNA strand breaks occur, activating a poly(adenosine-diphosphate-ribose) polymerase, which results in the in-tracellular depletion of nicotinamide adenine dinucleotide ( ) and adenosine triphosphate ( ). A Ca -dependent endonuclease then cleaves DNA into fragments, apoptosis.
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    Figure 3. 2-Chlorodeoxyadenosine ( ) enters the cell through an efficient transport system where it resists (‡) deamination by adenosine deaminase ( ). The high ratio of deoxycytidine kinase ( ) to 5′-nucleotidase ( ) favors the formation of 2-chlorodeoxyadenosine monophosphate ( ), -diphosphate ( ), and -triphosphate ( ). In dividing cells, excess 2-CdATP inhibits ribonucleotide reductase ( ) with resultant inhibition of DNA synthesis. In resting cells, DNA strand breaks occur, activating a poly(adenosine-diphosphate-ribose) polymerase, which results in the in-tracellular depletion of nicotinamide adenine dinucleotide ( ) and adenosine triphosphate ( ). A Ca -dependent endonuclease then cleaves DNA into fragments, apoptosis. 2-Chlorodeoxyadenosine mechanism of action.2-CdAADADCK5′-NT2-CdAMP2-CdADP2-CdATPRNRNADATP++/Mg++

    2-Chlorodeoxyadenosine is unique compared with traditional antimetabolites in being equally active against both dividing and resting cells [11, 12]. A different mechanism of action must therefore operate in resting cells because ribonucleotide reductase is only expressed at low levels. The DNA strand breaks that gradually accumulate with time activate two enzyme systems: poly-(ADP-ribose) polymerase-consuming nicotinamide adenine dinucleotide and adenosine triphosphate [12, 13] and a Ca++/Mg++-dependent endonuclease that produces double-stranded DNA breaks at internucleosomal regions [14]. The cleavage of DNA into oligonucleosomal fragments follows, which is the hallmark of apoptosis, a form of programmed cell death [15-17].

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    Apoptosis

    Distinct from necrosis, apoptosis is a physiologic mechanism of cell death [18]. It is the mechanism by which senescent or abnormal cells that could interfere with organ function or develop into cancer are removed. Morphologically, apoptosis is characterized by compaction of chromatin against the nuclear membrane, cell shrinkage, and nuclear and cytoplasmic budding to form membrane-bound fragments, called apoptosis bodies, which are phagocytosed by adjacent cells or macrophages [17]. This process is completed in the absence of inflammatory changes. The tendency of a cancer cell to undergo apoptosis may determine the sensitivity of tumors with low growth fractions to chemotherapy. Indolent lymphoid tumors have high expression of the bcl-2 oncogene, known to enhance cell survival through its interference with apoptosis [19]. The induction of apoptosis by 2-CdA stimulates even greater interest in this agent for potential use in these bcl-2 expressing lymphoid malignancies. A possible relation between the expression of bcl-2 and susceptibility of the malignant cell to 2-CdA is under study.

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    Preclinical Studies and Pharmacologic Features

    Preclinical studies showed that both B- and T-lymphoblastoid cell lines were sensitive to 2-CdA but that T-lymphoblastoid cell lines were more vulnerable [6]. Clinically, this difference is not apparent, and, in fact, B- lymphocyte-derived disorders are highly responsive. Prolonged exposure of resting peripheral blood lymphocytes to 2-CdA in vitro resulted in greater lymphocytotoxicity than did brief incubations [20], which led to the selection of a continuous intravenous infusion schedule for the initial clinical trials.

    The single 50% lethal dose of 2-CdA given intraperitoneally to mice was 150 mg/kg body weight and with daily administration for 5 days, the 50% lethal dose was 100 mg/kg [21]. 2-Chlorodeoxyadenosine prolonged the life of mice with L1210 leukemia [6]. Doses of 1 mg/kg given by continuous intravenous infusion to monkeys for 7 days caused severe diarrhea and granulocytopenia. 2-Chlorodeoxyadenosine is cleared by mammalian kidneys, probably secreted through the renal organic cation carrier system, and its elimination is according to a two-compartment model, with α −and β-half-lives of 35 minutes and 6.7 hours, respectively [22]. Plasma 2-CdA concentrations of 20 to 30 nmol in patients with lymphoid malignancies were achieved with the standard infusion dose of 0.1 mg/kg per day by continuous infusion, which exceeds the 50% inhibition of growth for some human malignant lymphoblast cell lines incubated with 2-CdA in vitro [20].

    A bolus method of 2-CdA administration was developed based on pharmacokinetic studies showing high concentrations and prolonged intracellular retention of 2-chlorodeoxyribonucleotides in chronic lymphocytic leukemia [23]. This method of drug delivery was devised to facilitate the outpatient administration of 2-CdA and to avoid the need for central catheters and infusion devices [24]. The bioavailability of 2-CdA given subcutaneously is 100% and, when administered orally, is 50%, although there are considerable differences among patients. Oral absorption is not enhanced by suppression of gastric acid [25]. 2-Chlorodeoxyadenosine penetrates the cerebrospinal fluid [26] with levels that are 25% of the plasma levels [27].

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    Clinical Studies—Phase 1

    2-Chlorodeoxyadenosine dose-escalation studies showed myelosuppression, with considerable hematopoietic stem cell toxicity to be dose limiting. A maximum tolerated dose of 0.1 mg/kg per day for 7 days by continuous infusion (using the conversion factor of 40, 0.1 mg/kg is equivalent to 4 mg/m2[28]) was established and was associated with a 25% incidence of myelosuppression [20]. Single courses of the drug at this dose caused transient marrow suppression with granulocytopenia and thrombocytopenia, especially in patients who were pancytopenic before the start of 2-CdA therapy. When repeated courses of 2-CdA were administered, cumulative thrombocytopenia became the limiting toxicity in 20% to 30% of patients, which persisted in some patients for more than 6 months. At this dose, no nausea, vomiting, alopecia, nephrotoxicity, hepatotoxicity, pulmonary and cardiac toxicity, or neurotoxicity was observed. Severe and sometimes irreversible nephrotoxicity and neurotoxicity with paresis were encountered when 2-CdA was administered at 0.4 to 0.5 mg/kg (16 to 20 mg/m2) per day for 7 to 14 days by continuous infusion in combination with high-dose cyclophosphamide and total body irradiation in preparation for allogeneic bone marrow transplantation. The contribution of 2-CdA compared with total body irradiation or high-dose cyclophosphamide in conjunction with the 2-CdA to these toxicities is unclear. In the initial studies, the actual dose of 2-CdA administered to patients was 0.09 mg/kg per day because doses were standardized using the extinction coefficient of chloroadenine, which proved to be slightly lower than that of 2-CdA [29]. Subsequently, all patients received 0.1 mg/kg per day because of synthesis and formulation changes, representing most patients treated in the clinical development of this drug.

    The maximum tolerated dose for 2-CdA delivered as a 7-day intravenous infusion to patients with nonhematologic malignancies was also 0.1 mg/kg per day. Neurologic events occurred in two patients, both with malignant melanoma, one treated with 0.15 mg/kg per day of 2-CdA and the other with 0.2 mg/kg per day. A direct neurotoxic role for 2-CdA was not absolutely established because of other associated conditions [26], and further studies are ongoing to define if and at what dose neurotoxicity occurs with 2-CdA treatment. Ongoing dose-escalation studies in adults with resistant acute myeloid leukemia (5 to 21 mg/m2 body surface area per day [0.13 to 0.53 mg/kg per day] for 5 days by continuous infusion, 2.5 to 21.5 mg/m2 per day [0.06 to 0.54 mg/kg per day] for 5 days over 1 hour, and 4 to 10.8 mg/m2 per day [0.1 to 0.3 mg/kg per day] for 7 days by continuous infusion) have thus far shown the absence of non–hematologic-related toxicity, although the maximum tolerated dose has not yet been attained [30, 31].

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    Clinical Studies—Phase II

    Once the phase I studies had shown 0.1 mg/kg per day of 2-CdA by continuous infusion for 7 days to be the safe and effective dose, various indolent lymphoproliferative disorders were evaluated for efficacy (Table 1).

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    Table 1. Clinical Activity of 2-Chlorodeoxyadenosine

    Chronic Lymphocytic Leukemia

    This disease is caused by the proliferation and accumulation of B lymphocytes. There are 10 000 new cases per year in the United States. Because all therapy is palliative with no advantage to the early institution of systemic therapy, treatment indications include disease-related symptoms, progressive marrow failure (anemia, thrombocytopenia), immune cytopenias, massive splenomegaly, or bulky lymphadenopathy. The alkylating agent chlorambucil, with or without prednisone, is the standard initial treatment [32]. Several trials have shown that single-agent fludarabine has clinically significant activity in treating patients with alkylator-refractory chronic lymphocytic leukemia [3, 33-36].

    The activity of 2-CdA in patients who have failed alkylating agents for chronic lymphocytic leukemia was first reported in 1988 [37]. Ninety patients with refractory chronic lymphocytic leukemia were treated with 2-CdA administered as either a 0.1 mg/kg per day 7-day continuous intravenous infusion or as a 0.028 to 0.14 mg/kg per day 2-hour bolus for 5 days [24]. Eighty-two patients had Binet stage C disease. Four patients (4%) had complete responses, and 36 (40%) had partial responses. Of the 50 patients who did not meet response criteria, 27 (54%) had a 50% or greater sustained reduction in the absolute lymphocyte count. The ratio of deoxycytidine kinase to cytoplasmic 5′-nucleotidase, the enzymes that phosphorylate 2-CdA and dephosphorylate 2-CdA-5′-monophosphate, respectively, was predictive of 2-CdA responsiveness [38]. Recently, it was reported that of 18 previously treated patients with chronic lymphocytic leukemia treated with five daily 2-hour intravenous infusions of 0.12 mg 2-CdA/kg given monthly, 7 (39%) achieved complete responses and 5 (28%) had partial responses [39]. This higher response rate may be related to the inclusion of fewer patients with stage C disease and the administration of a median of four 2-CdA courses compared to two in the Scripps Clinic trial [24]. Four patients with chronic lymphocytic leukemia from Sweden who failed fludarabine therapy were reported to be sensitive to 2-CdA action [40]. Three obtained partial responses and a single patient had a complete response. The experience in the United States in this cohort of patients was less favorable [41]. Among 14 such patients at Scripps Clinic, no responses were achieved, although 6 patients did have sustained reductions in their lymphocytosis. Of 28 patients with chronic lymphocytic leukemia refractory to fludarabine who were treated with 2-CdA, 2 (7%) had partial remissions, but anemia and thrombocytopenia were rarely corrected and were frequently made worse [42].

    Of 20 patients with previously untreated chronic lymphocytic leukemia who were administered 2-CdA as a 0.1 mg/kg per day 7-day continuous infusion every 28 to 35 days for a median of four courses, 5 patients achieved complete responses (25%) and 12 patients achieved partial responses (60%), for an overall response rate of 85% [43]. These results establish the major activity of 2-CdA in patients with previously untreated chronic lymphocytic leukemia. This finding tends to confirm the hypothesis that the lower response rates seen in previously treated patients is in part caused by poor marrow reserve from previous treatment, because almost all of these patients had a sustained decrease in their lymphocytosis despite insufficient improvement in hemoglobin concentration or platelet count to achieve a response status.

    Hairy Cell Leukemia

    This chronic B-cell lymphoproliferative disorder is characterized by cells that exhibit cytoplasmic projections and that have a typical pattern of infiltration in the marrow and spleen [44]. In 1990, the first 12 patients treated with a single 7-day course of 2-CdA were described [45]. Since that report was published, more than 380 patients have been treated at Scripps Clinic. Of the first 144 patients similarly treated and followed for a median of 14 months, 123 (85%) obtained complete responses, 17 (12%) had partial responses, 3 (2%) did not respond, and 1 patient died of a cardiovascular event and was therefore unevaluable [46]. Responses were independent of previous therapy and disease duration. At a median follow-up of 36 months after treatment, four patients have had relapses. The relapses were typically characterized by stable hematologic parameters and minimal hairy cell leukemic involvement of the marrow during the months of follow-up. Other single-institution studies have documented similar response rates [47-51]. More recently, it was shown that some patients in apparent complete remission after 2-CdA therapy have minimal residual disease by immunohistochemical staining [52] and by polymerase chain reaction [53] done on serial marrow biopsy specimens. Patients need to be observed longitudinally to determine if minimal residual disease detection by these sensitive techniques is predictive of relapse and if the persistence of minimal residual disease negatively affects long-term outcome.

    Fever was the principal toxicity, occurring in 63 (43%) patients, and appeared to be related to lysis of hairy cells. Documented infections not related to central catheters were uncommon, occurring in only four patients. 2-Chlorodeoxyadenosine is immunosuppressive. The number of both T and B lymphocytes was reduced after 2-CdA and both CD4 and CD8 T lymphocytes were affected. A decrease in the CD4/CD8 ratio due to slower recovery of CD4 cells was observed [54]. Some studies have shown a tendency toward restoration of T-cell subsets in most patients between 6 and 12 months after 2-CdA administration [54, 55], whereas others have shown CD4 lymphocytopenia beyond 2 years [56]. Long-term follow-up, however, has shown no evidence of increased late infections or secondary malignancies.

    Five patients with hairy cell leukemia resistant or intolerant to 2′-deoxycoformycin were treated with 2-CdA [57]. Four patients obtained complete responses with a median follow-up of more than 11 months, suggesting a lack of cross-resistance between these two nucleosides in hairy cell leukemia. 2-Chlorodeoxyadenosine is emerging as the treatment of choice for this disease, given its favorable toxicity profile, high efficacy, and low relapse rate after a single 7-day course. In an attempt to eliminate the need for central venous catheters and infusion devices, 18 patients received 2-CdA at 4 mg/m2 daily for 7 days by subcutaneous injection [58]. Fifteen patients (83%) achieved complete responses and 2 had partial responses. Protracted follow-up is needed to determine whether this route of administration is equivalent to the present route and schedule given the high response rates.

    Low-Grade Non-Hodgkin Lymphoma

    Forty patients with previously treated low-grade lymphoma were treated with 2-CdA at 0.1 mg/kg per day by continuous infusion for 7 days [59]. An overall response rate of 43% was achieved, with 8 patients having complete responses and 9 patients having partial responses. Interestingly, histologic findings and previous therapy did not correlate with response. Myelosuppression was the principal toxicity, with 18% of patients developing neutropenia and 30%, thrombocytopenia. The nadir of neutrophil counts occurred between 7 and 14 days after therapy, and recovery to baseline values usually occurred by 28 days after therapy. The nadir of the platelet count occurred between 7 and 21 days after therapy, and recovery of platelet counts occurred between 28 and 42 days after therapy. Evidence of cumulative myelosuppression occurred with 2-CdA therapy, which was more severe and longer in those patients more heavily pretreated. 2-Chlorodeoxyadenosine is currently under evaluation at our institution for patients with relapsed or refractory disease in combination with mitoxantrone, and in untreated patients as a single agent by the Cancer and Leukemia Group B.

    Two courses of 2-CdA at 0.1 mg/kg per day for 7 days by continuous infusion were administered to 29 patients with Waldenstrom macroglobulinemia [60]. Seventeen (59%) patients responded, and all 9 previously untreated patients met response criteria. With a median follow-up of 7 months, only 1 responding patient has had a relapse.

    Cutaneous T-Cell Lymphoma

    Of 15 patients with cutaneous involvement by T-cell lymphoma treated with 2-CdA, 3 (20%) achieved complete responses and 4 (27%) had partial responses, for a median response duration of 5 months [61]. Myelosuppression was again the major toxicity, occurring in 8 of 15 (53%) patients, and was more common in patients with mycosis fungoides than with nonmycosis fungoides histologic findings as well as in the more heavily pretreated patients. Similar responses and toxicities have been documented by other investigators [62, 63].

    Prolymphocytic Leukemia and Multiple Myeloma

    2-Chlorodeoxyadenosine has been reported to have activity in single patients with B-cell prolymphocytic leukemia [64] but lacks activity in patients with multiple myeloma [65].

    Myeloid Leukemias

    Of 17 children with refractory acute myeloid leukemia treated with 2-CdA at 8.9 mg/m2 per day for 5 days by continuous infusion at St. Jude Children's Research Hospital, 8 obtained complete responses (4 after a single course) and 2, partial responses [66, 67]. Ongoing dose-escalation studies in adults with resistant acute myeloid leukemia (5 to 21 mg/m2 for 5 days by continuous infusion) [30], 2.5 to 25 mg/m2 per day for 5 days over 1 hour [31] and 4 to 10.8 mg/m2 per day for 7 days by continuous infusion have thus far shown no substantial antileukemic effect, although maximum tolerated doses have not yet been reached.

    In vitro clonal growth studies show that immature myeloid progenitors from normal marrow are markedly inhibited by 2-CdA [68]. Accordingly, 2-CdA was administered to 12 patients with Philadelphia chromosome-positive chronic myeloid leukemia [69]. Ten patients achieved complete hematologic responses and 2 achieved partial hematologic responses after a median of two 2-CdA courses. The median first hematologic response duration was 3 months. Of the 7 patients who had relapses, 5 obtained responses (4 had complete hematologic responses and 1 had a partial hematologic response) after a median of two further 2-CdA courses, with a median second hematologic response duration of 4 months. No patient had substantial suppression of the Philadelphia chromosome. Reversible myelosuppression and severe cumulative T-cell immunosuppression associated with opportunistic infections in 3 patients, all with CD4 lymphocytic counts less than 200 cells/mL, were the principal toxicities. The mechanism of action of 2-CdA in myeloid leukemias remains to be elucidated because only low levels of deoxycytidine kinase are expressed in granulocytes [6, 70].

    Miscellaneous Conditions

    Two of 7 patients with astrocytomas responded to 2-CdA [26]. Single patients with Hodgkin disease [71], Coombs-positive autoimmune hemolytic anemia unrelated to a lymphoproliferative disorder [71], and histiocytosis X [72] have shown responsiveness to single-agent 2-CdA therapy. Seven patients with chronic refractory immune thrombocytopenic purpura were resistant [73].

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    Conclusions and Future Strategies

    2-Chlorodeoxyadenosine has been identified through the studies we have discussed to have prominent activity against various lymphoid and, more modestly, against myeloid malignancies. Its effect on the low-grade lymphoid neoplasms has been greatest because of its unique property of potent cytotoxicity against nondividing cells. Although long-term survival studies are needed to determine the effect of 2-CdA on survival and curability in hairy cell leukemia, the dramatic and durable results achieved with a single infusion of therapy seem destined to alter the course of this disease.

    As part of a class of newer purine analogs, 2-CdA, along with 2′-deoxycoformycin and fludarabine, provides new therapeutic opportunities in the treatment of lymphoproliferative diseases. Where there was no standard second-line therapy after treatment with alkylator drugs, these agents are rapidly emerging as standard second-line therapy in various diseases, including chronic lymphocytic leukemia and non-Hodgkin lymphoma.

    Despite the favorable results we have outlined, we still do not fully understand the optimal ways to use these newer purine analogs. Further clinical research to refine schedules and routes of administration are needed. The appropriate strategies to combine these agents with other chemotherapeutic agents and biological response modifiers will be pioneered, and full characterization of the prominent immunosuppression that follows the administration of these drugs will be required. The important clinical question of cross-resistance between these purine analogs must be addressed in large, properly designed trials and in laboratory and clinical work done to determine if there is any rationale for simultaneous or sequential combinations of newer purine analogs. Although the structural homology between these molecules is great, each has unique clinical properties that might be exploited for efficacy or toxicity advantage.

    Among newer purine analogs, 2-CdA has favorable comparative efficacy and toxicity. It may be the only one of these drugs where myeloablation can be achieved without other organ toxicity, lending applicability to the bone marrow transplant setting. Studies taking advantage of the DNA repair inhibition properties of 2-CdA are currently under way using the drug in combination with DNA-damaging agents, such as mitoxantrone, alkylating drugs, and radiation.

    The development of new derivatives and oral formulations of 2-CdA should facilitate drug delivery [74]. Recently, the fluorinated derivative of 2-CdA was found to be effective when administered in a murine chronic lymphocytic leukemia model [75]. The marked sensitivity of monocyte function and survival to 2-CdA in vitro, together with the monocyte depletion in patients with rheumatoid arthritis receiving 2-CdA [76], suggests that 2-CdA may offer a novel therapeutic strategy for chronic inflammatory and autoimmune diseases characterized by inappropriate monocyte deployment or function. In patients with progressive multiple sclerosis, believed to be an autoimmune disorder, 2-CdA appeared to favorably alter the clinical course [77].

    Understanding the pathogenesis of rare diseases has furthered many advances in medicine. Elucidation of the mechanism for lymphopenia in children with severe combined immunodeficiency disease provided the impetus for the development of 2-CdA, now known to be a drug of powerful clinical usefulness, exemplifying the paradigm of rational drug development.

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