Original Article
Response to 2-Chlorodeoxyadenosine in Patients with B-Cell Chronic Lymphocytic Leukemia Resistant to Fludarabine
N Engl J Med 1992; 327:1056-1061October 8, 1992
- Abstract
- Abstract
Background.
Patients with untreated B-cell chronic lymphocytic leukemia have a high rate of complete remission when given the halogenated nucleoside analogue fludarabine. However, patients in whom the disease has proved refractory to primary treatment have a reduced life expectancy and a dismal outcome.
Methods.
We treated four consecutive patients who had unsatisfactory responses to second-line or subsequent treatment with fludarabine with another halogenated nucleoside analogue, 2-chlorodeoxyadenosine.
Results.
One patient with progressing lymphocytosis, anemia, and thrombocytopenia despite 10 courses of fludarabine entered a complete remission when treated with 2-chlorodeoxyadenosine. Two patients who had less-than-partial remissions after six courses of fludarabine had good partial remissions when treated with 2-chlorodeoxyadenosine. One patient with Coombs-positive hemolytic anemia who had no response to three courses of fludarabine had a partial remission, with resolution of hypogammaglobulinemia, when treated with 2-chlorodeoxyadenosine.
Conclusions.
There was no evidence of cross-resistance between fludarabine and 2-chlorodeoxyadenosine despite their similar structures. 2-Chlorodeoxyadenosine may induce a complete remission in chronic lymphocytic leukemia that is highly resistant to chemotherapy, and it deserves wider clinical evaluation in patients with this condition. (N Engl J Med 1992;327:1056–61.)
Media in This Article
Figure 1
Chemical Structure of 2-Chlorodeoxyadenosine and Fludarabine.Figure 2
Blood Lymphocyte Counts, Hemoglobin Levels, and Platelet Counts in Relation to Treatment with 2-Chlorodeoxyadenosine (CdA) in Patient 4.Article Activity
- Article
B-CELL chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. The initial management of this disorder is not complicated, since a high proportion of the patients have an asymptomatic disease with slow progression, and those with symptomatic disease often respond to low doses of oral alkylating agents. However, the disease remains incurable, since resistance to alkylating agents used with or without anthracyclines frequently develops. Although elderly people may die with CLL rather than from it, the vast majority of patients have a reduced life expectancy because of their leukemia.
The most important improvement in therapy during the 1980s was the introduction of the halogenated nucleoside analogue fludarabine monophosphate.1 Of 36 previously untreated patients in the first reported series,2 75 percent entered complete remissions according to established criteria.3 Among 68 previously treated patients, the rate of complete remissions was 29 percent, and that of partial remissions was 28 percent.2 Among the first 236 patients given the drug according to a protocol designed by the National Cancer Institute, the corresponding rates were 2 percent and 35 percent, respectively.4
2-Chlorodeoxyadenosine is a nucleoside analogue5 similar to fludarabine (Fig. 1Figure 1
Chemical Structure of 2-Chlorodeoxyadenosine and Fludarabine.). Both are adenine-based compounds in which halogen atoms are substituted at the 2 position, which makes them resistant to deamination by adenosine deaminase. The sugar part of the molecules differs in one position (2′), distinguishing the deoxyribose of 2-chlorodeoxyadenosine from the arabinose of fludarabine. The phosphate group on the 5′ position of the arabinose has the sole function of making fludarabine water-soluble, and this group is immediately cleaved in plasma. In contrast, 2-chlorodeoxyadenosine can be dissolved in phosphate-buffered saline.To exert its effect, 2-chlorodeoxyadenosine has to be phosphorylated intracellularly to its 5′ triphosphate (CdATP) by deoxycytidine kinase. Incorporation of CdATP into DNA stops chain elongation by DNA polymerase β6 and causes breaks in single-strand DNA, inhibition of DNA repair, poly(adenosine diphosphate)ribosylation, depletion of nicotinamide adenine dinucleotide and adenosine triphosphate, and cell death. Lymphoid cells have a higher level of activity of deoxycytidine kinase and are more sensitive to the toxic effects of deoxyribonucleotides than other types of cells, and thus the effects on nonlymphoid cells are limited. A unique feature of 2-chlorodeoxyadenosine is its high level of cytotoxic activity against resting cells,7 which is very useful in the treatment of indolent lymphoproliferative disorders.
2-Chlorodeoxyadenosine is probably the agent most effective against hairy-cell leukemia.8 , 9 In the first report of patients with CLL treated with 2-chlorodeoxyadenosine, only 4 of 18 patients (22 percent) had partial remissions and none had complete remission,10 but in a series of 80 patients treated at the Scripps Clinic, 3 (4 percent) had complete remissions and 38 (48 percent) had partial remissions.11 Thus, as therapy for CLL, fludarabine seemed to be superior to 2-chlorodeoxyadenosine.
We report on four consecutive patients with CLL who had little or no response to fludarabine but who all responded well to 2-chlorodeoxyadenosine. There was no cross-resistance between these structurally related nucleoside analogues.
Methods
Fludarabine Treatment
We studied four consecutive patients with previously treated B-cell CLL who had less-than-partial remissions when given fludarabine as second-line or subsequent treatment according to the National Cancer Institute group C protocol4 for refractory disease. Their clinical data are summarized in Table 1Table 1
Clinical Data on Four Patients with CLL.. Phenotyping was performed with a panel of monoclonal and immunoglobulin heavy-chain and light-chain antibodies and a flow cytometer (FACStar, Becton Dickinson, Mountain View, Calif.). The karyotype of leukemic cells stimulated by B-cell mitogen was assessed as previously described12: Patients 2 and 4 had karyotypes indicating a poor prognosis.13 All four patients had received 25 mg of fludarabine per square meter of body-surface area daily for five days, with the regimen repeated every fourth week. In Patient 4, lymphocyte counts decreased after two courses of fludarabine, but during eight further courses progressive anemia requiring frequent transfusions developed, with progressive lymphocytosis and thrombocytopenia; thus, the patient had clinical stage C disease as defined by Binet et al.14 Patients 1 and 2 had received six courses of fludarabine. Patient 1 had stable stage B disease, with an unchanged lymphocytosis (>50×109 cells per liter), generalized peripheral and abdominal lymphadenopathy, and general symptoms including night sweats, after undergoing the six courses. In Patient 2, fludarabine almost normalized the peripheral-blood cell counts; however, residual leukemia was revealed by flow cytometry, the bone marrow remained leukemic, and the disease remained in stage B, since the lymphadenopathy of the neck and the abdomen and the splenomegaly persisted unchanged. Patient 3, who had previously had episodes of pneumonia and well-controlled ulcerative colitis, had Coombs-positive hemolytic anemia; a hemolytic crisis that led to stage C disease developed after the first course of fludarabine. The hemolysis was partly resolved by long-term prednisone treatment (1 mg per kilogram of body weight), but the lymphocytosis had not decreased after three courses of fludarabine, and thus the patient was considered to have no response.2-Chlorodeoxyadenosine Treatment
The 2-chlorodeoxyadenosine was prepared from a dry powder (a gift from Dr. Ernest Beutler, Scripps Clinic and Research Foundation, La Jolla, Calif). Treatment was started between one and two months after the last course of fludarabine. Each patient received 0.12 mg per kilogram daily as two-hour intravenous infusions during five consecutive days. The courses were repeated about monthly. This total dose of 0.6 mg per kilogram per course was identical to the actual dose per course in previous studies, as discussed by Beutler.15 The study was registered in the United States and was approved by the Swedish Medical Products Agency and the ethics committee at Huddinge Hospital.
Criteria for Response
The response criteria used were those recommended by the Work Group sponsored by the National Cancer Institute.3 A complete remission was indicated by the following: hemoglobin levels above 110 g per liter, blood lymphocyte counts below 4×109 per liter, platelet counts above 100×109 per liter, and neutrophil counts above 1.5×109 per liter, all present for two months; the absence of constitutional symptoms and organomegaly; and less than 30 percent lymphoid cells among the nucleated cells of the bone marrow, with or without nodules. A partial remission was indicated by a decrease of more than 50 percent in the blood lymphocyte count and the degree of organomegaly, and a decrease of at least 50 percent in the degree of anemia, thrombocytopenia, and neutropenia.
Results
Infusion of 2-chlorodeoxyadenosine was very well tolerated, and no patient experienced nausea, vomiting, or hair loss. All four patients responded with normalization of the blood lymphocyte count. In Patient 4, more than 50×109 leukemic cells per liter were cleared within two weeks after the start of the first course of 2-chlorodeoxyadenosine, the thrombocytopenia resolved within three months, and the anemia resolved in six months (Fig. 2Figure 2
Blood Lymphocyte Counts, Hemoglobin Levels, and Platelet Counts in Relation to Treatment with 2-Chlorodeoxyadenosine (CdA) in Patient 4.). To reduce iron overload due to transfusions, the patient underwent phlebotomy twice during and after the sixth course, without problems. Bone marrow aspirations had been dry, yielding densely packed marrow, but produced fluid marrow four months after the first course of 2-chlorodeoxyadenosine. A complete remission was achieved after five courses, with normal marrow and residual small nodules (Table 2Table 2
Morphologic Features of Bone Marrow in the Four Patients with CLL.). At that time, flow cytometry of bone marrow cells showed 15 percent lymphoid cells, of which 35 percent were CD19+, 13 percent κ+, and 2 percent λ+; two months after the sixth course, cytometry showed 12 percent lymphoid cells. Repeated karyotype analysis showed no clonal abnormality, but 1 of 14 cells studied had trisomy 18 and another had a 14q— marker chromosome. There was thus no evidence of leukemia, but minimal bone marrow abnormalities persisted. Peripheral-blood stem cells primed with cyclophosphamide (2 g per square meter) and filgrastim (granulocyte colony-stimulating factor [Neupogen]) were then removed, and a seventh course of 2-chlorodeoxyadenosine was given. The patient underwent high-dose chemotherapy with support from infusions of autologous stem cells. The side effects of 2-chlorodeoxyadenosine therapy included pneumococcal pneumonia, which responded to penicillin given after the first course of treatment, and thoracic dermatomal herpes zoster after the third course.Two of the patients had lymphadenopathy. This symptom resolved completely in Patient 2; in Patient 1, however, the peripheral lymphadenopathy resolved but minimal lymphadenopathy persisted, as demonstrated by abdominal CT scanning. The lymphocyte counts were found to be reduced in both patients on bone marrow examination (Table 2), but residual leukemic cells were detected by flow cytometry. After repeated courses of 2-chlorodeoxyadenosine, asymptomatic thrombocytopenia developed in both patients, with platelet counts of 50×109 per liter in Patient 2 and 70×109 per liter in Patient 1; the counts slowly returned to about 90×109 per liter when therapy was discontinued. Because of the thrombocytopenia, treatment was not carried to the point of eliminating leukemic cells from the bone marrow. There were no infections. Minimal peripheral lymphadenopathy recurred in both patients nine months after treatment stopped. At present, they have not received treatment for 15 months.
Patient 3 had a partial remission (<4×109 CD19+ cells per liter in peripheral blood) after two courses of 2-chlorodeoxyadenosine, and the hemolytic anemia resolved completely, with no further need of steroids. Bone marrow aspiration showed no reduction in the lymphocyte count. However, of the 52 percent CD19+ cells present, only 2 percent were positive for both CD19 and CD5, and the ratio of κ+ to λ+ cells was normal — 20 percent to 6 percent — indicating that some of these cells were not leukemic but normal B cells. The hypogammaglobulinemia resolved (Fig. 3Figure 3
Blood Lymphocyte Counts and Haptoglobin and Immunoglobulin Levels in Relation to Treatment in Patient 3.). After two more courses, cytopenia gradually developed and then another episode of pneumonia. Staphylococcus epidermidis septicemia developed. Five months after the last course of 2-chlorodeoxyadenosine the blood lymphocyte count rose to 9×109 per liter, with no improvement in the anemia and thrombocytopenia, and two months later the patient died with pneumonitis and peritonitis secondary to ulcerative colitis. Adenovirus type 1 was isolated from lung tissue obtained at autopsy. At the time of relapse the gamma globulin levels again decreased (Fig. 3).The effect of 2-chlorodeoxyadenosine on the lymphocyte subpopulations is shown in Figure 4Figure 4
Absolute Blood Counts of CD19+, CD8+, and CD4+ Lymphocytes during and after 2-Chlorodeoxyadenosine Treatment..Discussion
The four patients with advanced CLL described here all responded well to 2-chlorodeoxyadenosine despite the resistance of their disorder to the structurally very similar fludarabine. None had previously had a remission of a similar quality when given conventional chemotherapy. At the time of relapse, all had received fludarabine until they had a maximal response or disease progression; they then were given 2-chlorodeoxyadenosine. Thus, we do not believe that similar responses could have been achieved by continuing fludarabine therapy. The patients were consecutive and were selected to receive 2-chlorodeoxyadenosine because of their continuing need for therapy after prolonged fludarabine treatment.
The response to 2-chlorodeoxyadenosine always included normalization of the blood lymphocyte count, peripheral lymphadenopathy, and general symptoms. Patient 4 had a true complete remission after 2-chlorodeoxyadenosine treatment, and Patients 1 and 2 had good partial remissions of better quality and longer duration than those induced with previous treatment. Patient 3 had a partial remission with resolution of hemolysis after he received 2-chlorodeoxyadenosine without steroid treatment; he also had an increase in the number of polyclonal normal B cells in the marrow and relief of hypogammaglobulinemia (Fig. 3), an uncommon response to chemotherapy in patients with CLL. Additional courses induced severe cytopenia and further immune suppression, leading to fatal pneumonitis due to adenovirus type 1. This rare infection also occurred in another patient with refractory CLL, who had neutropenia after chemotherapy that included cyclophosphamide, mitoxantrone, vincristine, and prednisone.16
The dose-limiting toxic effects of 2-chlorodeoxyadenosine are thrombocytopenia and infection. The infections might be related to lymphocytopenia, since none of the patients studied had neutropenia. There was no selective depletion of a specific T-cell subset (Fig. 4). The leukemic cells appeared to be more sensitive to 2-chlorodeoxyadenosine than did the T cells.
These responses might have been due to a synergy between fludarabine and the subsequent 2-chlorodeoxyadenosine treatment. However, patients may have such responses even though they have not been treated with fludarabine. Of six previously treated patients with CLL who received 2-chlorodeoxyadenosine without previous fludarabine therapy, two had complete remissions (with no residual leukemic cells in the bone marrow according to flow cytometry) and two had partial remissions17 (and unpublished data). Another patient whose lymphocytes had undergone prolymphocytic transformation, as well as a recently treated patient in whom CLL progressed during fludarabine treatment, had no response to subsequent 2-chlorodeoxyadenosine therapy. Some patients have leukemia that is clearly resistant to 2-chlorodeoxyadenosine, even some who have received chlorambucil as the sole previous therapy. In other patients, 2-chlorodeoxyadenosine may reduce the number of tumor cells, without resolving cytopenia.
A median of two courses of 2-chlorodeoxyadenosine were given at the Scripps Clinic,11 and a median of four courses were given in our study (range, one to six). This difference is probably the most important reason for our seemingly better results. However, repeated courses may be hazardous, since patients may succumb to systemic fungal infections.9 Also, our patients received intermittent two-hour infusions of 2-chlorodeoxyadenosine,18 whereas most of the U.S. patients received seven-day continuous infusions.11 A recent study of the pharmacokinetics of 2-chlorodeoxyadenosine nucleotides within leukemic cells after intermittent infusion and continuous infusion showed that the areas under the concentration-versus-time curves were very similar19; intracellular drug levels were detectable more than a week after treatment. Intermittent infusion produces higher peak concentrations in leukemic cells, is more convenient and less expensive, and is probably not less effective. Since the pharmacokinetics of subcutaneously injected 2-chlorodeoxyadenosine is similar to that of the drug when infused intravenously for two hours, subcutaneous injections would be an even simpler way to administer the agent to outpatients.20
2-Chlorodeoxyadenosine seems to be an effective therapy in some patients with advanced CLL. Infections may be a problem, and thrombocytopenia might be dose-limiting. 2-Chlorodeoxyadenosine should be studied in patients with less advanced disease and less impaired hematopoiesis. The fact that both 2-chlorodeoxyadenosine20 and fludarabine21 seem to have sufficient bioavailability when given orally suggests that entirely oral administration of these drugs without alkylating agents may be possible in patients with the most common and the least curable form of leukemia.
Supported by the Swedish Cancer Foundation (Project 2409-B91–01XAB), the Swedish Society for Medical Science, the Karolinska Institute Research Funds, the Medical Research Council, and the Dagmar Ferb Memorial Fund.
We are indebted to Dr. Gunnar Grimfors (Stockholm) for referring Patient 4 to us.
Source Information
From the Division of Clinical Hematology and Oncology, Department of Medicine (G.J., J.L.), and the Department of Pathology (A.E.-R.), Huddinge Hospital, Huddinge, and the Department of Clinical Pharmacology, Karolinska Hospital, Karolinska Institute, Stockholm (J.L.), both in Sweden. Address reprint requests to Dr. Juliusson at the Department of Medicine, Huddinge Hospital, S-141 86 Huddinge, Sweden.
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