Original Article
Lack of Effect of 2-Chlorodeoxyadenosine Therapy in Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine Therapy
N Engl J Med 1994; 330:319-322February 3, 1994
- Abstract
Background
Fludarabine and 2-chlorodeoxyadenosine are nucleoside analogues that have proved effective in patients with chronic lymphocytic leukemia (CLL). Although their mechanism of action is thought to be similar, a small number of patients who do not respond to fludarabine do respond to 2-chlorodeoxyadenosine. The extent to which 2-chlorodeoxyadenosine is effective in patients who do not respond to fludarabine is not known, however.
Methods
We treated 28 patients with CLL refractory to fludarabine therapy with a continuous infusion of 2-chlorodeoxyadenosine at a daily dose of 4 mg per square meter of body-surface area for seven days. The treatment could be repeated monthly. The number of treatments ranged from one to five; patients who responded continued to receive treatment until the maximal response was achieved.
Results
Two patients (7 percent) had partial remissions, but no patients had complete remissions. One other patient had a substantial response but had residual thrombocytopenia. The rate of response in most affected organs was 20 percent, but anemia or thrombocytopenia rarely improved. Myelosuppression was frequent, and 65 percent of the courses of 2-chlorodeoxyadenosine therapy were accompanied by febrile episodes or infections. Ten patients died within 60 days of starting therapy with 2-chlorodeoxyadenosine; eight deaths were related to infection. The median platelet count at the start of 2-chlorodeoxyadenosine therapy in these 10 patients was 24,000 per cubic millimeter, as compared with 109,000 per cubic millimeter in the other 18 patients. Five patients were alive after a median follow-up of 24 months.
Conclusions
Patients with advanced CLL refractory to fludarabine therapy are unlikely to benefit from treatment with 2-chlorodeoxyadenosine. Although 20 percent of the patients have some response, thrombocytopenia and anemia are rarely corrected and may be made worse by 2-chlorodeoxyadenosine therapy.
Media in This Article
Figure 1
Kaplan-Meier Survival of Patients with CLL Resistant to Fludarabine Who Were Treated with 2-Chlorodeoxyadenosine.Table 1
Characteristics of 28 Patients with Refractory CLL Treated with 2-Chlorodeoxyadenosine.Article Activity
- Article
Nucleoside analogues such as fludarabine and 2-chlorodeoxyadenosine are new and effective therapies for indolent lymphoid cancers. Among previously treated patients with chronic lymphocytic leukemia (CLL), 57 percent respond to fludarabine and 27 percent have a complete remission1. The rate of response to 2-chlorodeoxyadenosine in previously treated patients with CLL is similar (44 percent), but only 4 percent have complete remissions2. Fludarabine is a fluorinated analogue of vidarabine with a phosphate molecule attached to the arabinose moiety. The structure of 2-chlorodeoxyadenosine is similar, differing only in the halogen attached to the purine ring (chloride instead of fluoride) and the lack of the phosphate group. Both drugs require phosphorylation for activity, both are substrates for DNA polymerase, and both are incorporated into growing DNA chains, inhibiting further elongation of the chains. They also decrease intracellular nucleotide pools by inhibiting ribonucleotide reductase3. In vitro, fludarabine and 2-chlorodeoxyadenosine induce morphologic and biochemical changes in CLL lymphocytes that are characteristic of programmed cell death (apoptosis)3,4. Their similar structures and activities suggest that cross-resistance is possible. The report that 2-chlorodeoxyadenosine induced a partial remission in one of six patients with CLL that was resistant to fludarabine, however, suggested a partial lack of cross-resistance between 2-chlorodeoxyadenosine and fludarabine,2 and subsequently Juliusson et al. described four consecutive patients with CLL who did not respond to fludarabine but did respond to 2-chlorodeoxyadenosine5. We summarize our results with 2-chlorodeoxyadenosine therapy in patients with CLL refractory to fludarabine therapy.
Methods
Patients
We treated 28 patients who had CLL that was refractory to fludarabine therapy with 2-chlorodeoxyadenosine. To be included in the treatment group, the patients had to have a Zubrod performance score of 2 or less, normal hepatic and renal function, and no response to treatment with fludarabine. The protocol was approved by the institutional review board, and all patients gave written informed consent. The characteristics of the patients are shown in Table 1Table 1
Characteristics of 28 Patients with Refractory CLL Treated with 2-Chlorodeoxyadenosine.. Their median age was 63 years (range, 43 to 80), and 21 (75 percent) were men. Eighty-two percent of the patients had advanced disease with anemia, thrombocytopenia, or both (Rai stage III or IV). The median length of time from diagnosis to treatment with 2-chlorodeoxyadenosine was 68 months (range, 6 to 139). All patients had received therapy with alkylating agents before being treated with fludarabine, and 19 patients (68 percent) had received other therapy in the interval between treatment with fludarabine and treatment with 2-chlorodeoxyadenosine. These other therapies included an anthracycline-based regimen (11 patients), cytarabine with cisplatin (2 patients), etoposide with or without mitoxantrone (7 patients), an alkylating agent (4 patients), and monoclonal-antibody-toxin therapy (2 patients). The median time from the last treatment to the initiation of 2-chlorodeoxyadenosine therapy was 1 month (range, 1 to 11). The median number of previous treatment regimens was 4 (range, 2 to 7).Twenty-five patients had disease that was refractory to initial treatment with fludarabine, defined as the failure to achieve at least a partial remission according to National Cancer Institute criteria after at least two courses. The median number of courses of fludarabine given was 5 (range, 2 to 19). Three patients had responses to fludarabine followed by relapse, and their disease was considered refractory to subsequent treatment. Seventy-five percent had a Zubrod performance score of 1 or less. The following median hematologic values were recorded at the start of therapy: white-cell count, 64,000 per cubic millimeter (range, 1000 to 228,000); hemoglobin level, 10.2 g per deciliter (range, 6.0 to 15.8); and platelet count, 83,000 per cubic millimeter (range, 13,000 to 437,000). Sixteen patients (57 percent) had hepatosplenomegaly, and lymphadenopathy was present at a median of 3 sites (range, 0 to 3).
Therapy
The patients received 2-chlorodeoxyadenosine as a continuous infusion at a daily dose of 4 mg per square meter of body-surface area for seven days on an outpatient basis. The courses could be repeated every 28 days. Fifteen patients (54 percent) received one course, eight patients (29 percent) received two courses, four patients (14 percent) received three courses, and one patient received five courses. Only one course was given because of progressive disease in six patients, infectious complications leading to a poor performance status in four patients, and death in five patients.
Response Criteria
The response criteria were those defined by the working group sponsored by the National Cancer Institute6. A complete remission was defined as the complete resolution of palpable lymphadenopathy and hepatosplenomegaly, a neutrophil count of at least 1500 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a hemoglobin level of at least 11.0 g per deciliter, a lymphocyte count of 4000 per cubic millimeter or less, and a bone marrow aspirate containing 30 percent or fewer lymphocytes. A partial remission was defined as the occurrence of at least a 50 percent decrease in all node-bearing areas and organ enlargement and at least a 50 percent improvement from base line in any abnormal hematologic values.
Results
Responses
The response could be evaluated in all patients. Two patients (7 percent) had partial remissions. One was a 55-year-old man who had evidence of remission on the basis of blood and bone marrow findings after fludarabine therapy, but only minor regression of lymphadenopathy. Six months later his white-cell count was 29,000 per cubic millimeter, and he had diffuse lymphadenopathy. He was treated with five courses of 2-chlorodeoxyadenosine, after which thrombocytopenia occurred. His platelet count had increased to more than 100,000 per cubic millimeter six months later. He had a relapse 14 months after the initiation of 2-chlorodeoxyadenosine therapy. The second patient with a partial remission was a 46-year-old man who responded to six courses of fludarabine but in whom splenomegaly persisted. Twenty-nine months later he had lymphadenopathy as well as splenomegaly and a white-cell count of 51,000 per cubic millimeter. He had a partial response after three courses of 2-chlorodeoxyadenosine and remained in partial remission four months after the start of therapy. Another patient treated with 2-chlorodeoxyadenosine, a 74-year-old man, had evidence of antitumor activity (decrease in bone marrow lymphocytes from 73 to 12 percent and a decrease in the neutrophil count from 40,000 to 3300 per cubic millimeter) but had persistent thrombocytopenia (platelet count, 58,000 per cubic millimeter). Six months later he had progression of CLL, but his platelet count had increased to 93,000 per cubic millimeter, suggesting that the worsening thrombocytopenia was drug-related.
2-Chlorodeoxyadenosine had some antitumor activity in other patients. In most of these patients, there was not improvement in all variables evaluated, and the criteria for remission were not met (Table 2Table 2
Response to 2-Chlorodeoxyadenosine as Assessed by Improvements in the Degree of Organ Involvement and Hematologic Abnormalities.). For organ involvement, about 20 percent of patients had responses at any site. The most obvious response was a 50 percent decrease in the absolute lymphocyte count, which occurred in 57 percent of the patients. Twenty-nine percent of patients had a one-log reduction in the absolute lymphocyte count. Only one patient with thrombocytopenia or anemia had at least a 50 percent improvement in these abnormalities; these abnormalities were at least in part due to drug toxicity, since thrombocytopenia is a well-described side effect of therapy with 2-chlorodeoxyadenosine. The overall median survival of the 28 patients was three months (Figure 1Figure 1Kaplan-Meier Survival of Patients with CLL Resistant to Fludarabine Who Were Treated with 2-Chlorodeoxyadenosine.).Toxicity
Ten patients (36 percent) died during the first two courses of 2-chlorodeoxyadenosine. Eight patients died of infection, and two patients died of intracerebral hemorrhage. Nine of these 10 patients had advanced disease with thrombocytopenia (Rai stage IV); the median initial platelet count for the group was 24,000 per cubic millimeter, as compared with a median count of 109,000 per cubic millimeter in the other 18 patients.
Myelosuppression was frequent with 2-chlorodeoxyadenosine; neutropenia and thrombocytopenia developed in the majority of patients (Table 3Table 3
Hematologic Toxicity of 2-Chlorodeoxyadenosine.). Nonhematologic toxicity was minimal. Three patients had increased fatigue or weakness. One patient reported numbness of the feet. Febrile episodes and infections were frequent (31 of 48 courses [65 percent]) in this group of heavily pretreated patients with advanced disease. Fever of unknown origin occurred during or after 10 courses (21 percent). Pneumonia or bacterial sepsis was noted in another 12 courses (25 percent). In one patient Pneumocystis carinii pneumonia and candida esophagitis developed. Minor infections occurred during or after nine courses of therapy (19 percent).Discussion
Fifty-seven percent of previously treated patients with CLL respond to therapy with fludarabine. However, once CLL becomes refractory to this therapy, the patients' prognosis is poor and few respond to other drugs or combinations of drugs1. 2-Chlorodeoxyadenosine is a deoxyadenosine analogue of vidarabine with lymphotoxic activity. It induces remissions in 89 to 100 percent of patients with hairy-cell leukemia and has activity in patients with CLL7,8. Among 18 patients with CLL whose disease was refractory to therapy with alkylating agents or who relapsed after such treatment, 4 had partial remissions after therapy with 2-chlorodeoxyadenosine9. In a follow-up study of 90 patients with CLL in relapse, 40 (44 percent) responded to 2-chlorodeoxyadenosine and 4 (4 percent) had complete remissions2. Of six patients who had not responded to fludarabine therapy, one had a partial remission and three had at least a 50 percent reduction in the absolute lymphocyte count after treatment with 2-chlorodeoxyadenosine. However, the structural similarity of fludarabine and 2-chlorodeoxyadenosine, as well as their similar pharmacologic and biologic effects, suggests that cross-resistance would be likely.
Recently, however, Juliusson et al. described four consecutive patients with CLL who had not responded to fludarabine therapy but who had a response to 2-chlorodeoxyadenosine5. In a larger study, the same group reported that 12 of 18 previously treated patients responded to 2-chlorodeoxyadenosine; 8 had received fludarabine therapy, although it was not stated whether they responded to fludarabine10. By contrast, in another study none of three patients with CLL refractory to fludarabine therapy who were treated with 2-chlorodeoxyadenosine had a response11. In this study, we treated 28 patients with fludarabine-resistant CLL with 2-chlorodeoxyadenosine, and 2 (7 percent) had a partial remission. When the response was analyzed according to the site of involvement, we found evidence of antitumor activity in about 20 percent of patients. However, anemia and thrombocytopenia were rarely corrected. These results confirm that nucleoside analogues have myelosuppressive actions. In patients with refractory disease it may be difficult to assess the individual contributions of therapy and disease to reductions in the platelet count. However, thrombocytopenia developed in five of the nine patients (56 percent) with normal platelet counts (<100,000 per cubic millimeter) during treatment with 2-chlorodeoxyadenosine.
The difference between our results and those of Juliusson et al.5 may be due to differences in the study populations or the dose schedule of 2-chlorodeoxyadenosine. Some of our patients had received therapy in the interval between fludarabine therapy and 2-chlorodeoxyadenosine therapy, including both patients who responded to 2-chlorodeoxyadenosine. A more relevant fact may be that 82 percent of our patients had advanced disease with bone marrow failure (anemia, thrombocytopenia, or both; Rai stage, III to IV). This makes any myelosuppressive therapy difficult to administer. Only one of the four patients described by Juliusson et al.5 had thrombocytopenia. The majority of our patients (53 percent) received only one course of 2-chlorodeoxyadenosine, mainly because of infection or death. In contrast, Juliusson et al. gave four to seven courses. However, patients who do not respond to fludarabine therapy are likely to have bone marrow failure and a poor tolerance of chemotherapy because the rate of response to fludarabine is inversely related to the stage of disease.
In this study 2-chlorodeoxyadenosine was given as a continuous infusion at a daily dose of 4 mg per square meter for seven days. Juliusson et al. gave a comparable dose of 2-chlorodeoxyadenosine (total, 0.6 mg per kilogram of body weight) as a two-hour intravenous infusion for five consecutive days5. In a study of the pharmacokinetics of 2-chlorodeoxyadenosine given by intermittent and by continuous infusion, the areas under the curve for the concentration plotted against the time were similar, although intermittent infusion produced higher peak concentrations12. In the case of fludarabine and cytarabine, there is no clear relation between plasma concentrations and the active intracellular triphosphates13,14. With fludarabine, there is also no relation between the intracellular triphosphate and response. Patients whose disease is refractory to fludarabine therapy have intracellular drug concentrations similar to those in patients who respond to fludarabine15. In a study of 2-chlorodeoxyadenosine by Saven et al.,2 21 of the 69 patients received intermittent rather than continuous 2-chlorodeoxyadenosine therapy for five days but had similar response rates.
In summary, patients with CLL refractory to fludarabine therapy often have bone marrow failure and are immunocompromised. Subsequent treatment with 2-chlorodeoxyadenosine results in substantial myelosuppression, frequent infections, and an inability to tolerate repeated courses. Thus, patients with CLL who have not responded to fludarabine therapy and who have poor bone marrow reserve have a low likelihood of entering remission if treated with 2-chlorodeoxyadenosine.
Source Information
From the Department of Hematology, Box 61, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, where reprint requests should be addressed to Dr. O'Brien.
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Full Text
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