Correspondence

2-Chlorodeoxyadenosine for Patients with B-Cell Chronic Lymphocytic Leukemia Resistant to Fludarabine

N Engl J Med 1993; 328:812-813March 18, 1993

Article

To the Editor:

Juliusson et al. (Oct. 8 issue)1 describe four patients with chronic lymphocytic leukemia (CLL) who responded well to 2-chlorodeoxyadenosine (one with a complete response and three with partial responses), although their disorder was resistant to a structurally similar compound, fludarabine. We certainly welcome these authors' encouraging observations; however, it cannot be inferred from the results in such a small number of patients that 2-chlorodeoxyadenosine will benefit many patients with fludarabine-resistant CLL. Our experience with 2-chlorodeoxyadenosine in patients with no response to fludarabine has been less satisfactory.

Three patients with CLL that had been heavily pretreated (one patient with stage B disease and two with stage C, as defined by Binet) were given fludarabine (25 mg per square meter of body-surface area per day for five days). They had no responses after 3, 9, and 10 monthly courses of fludarabine, respectively (response was defined according to the criteria recommended by the National Cancer Institute2). All three patients were then given 2-chlorodeoxyadenosine (4 mg per square meter per day for seven days, as a continuous infusion). Two patients received two courses of 2-chlorodeoxyadenosine, and one received three courses. The lymphocyte count of one patient fell promptly, and her lymphadenopathy decreased; however, she never met the criteria for a partial response. 2-Chlorodeoxyadenosine was withheld after three courses when confusion developed (a complication that has not previously been reported in patients treated with this drug and that is possibly unrelated to therapy). The other two patients had no decrease in their lymphocyte counts, and their lymph nodes remained stable. Our experience agrees with that of Saven et al.3.: of their six patients in whom fludarabine treatment had failed, one had a partial response after treatment with 2-chlorodeoxyadenosine, four had stable disease, and one had progressive disease.

Juliusson et al. suggest that repeated courses of 2-chlorodeoxyadenosine (up to six courses) may be the reason for their good results, but their data show that in three of their four patients, a steep decrease in the lymphocyte count was evident soon after the first course. We did not observe such a prompt response in two of our three patients. It seems unlikely that additional courses of 2-chlorodeoxyadenosine could have benefited these patients with apparently refractory disease. Studies involving more patients are needed to assess the therapeutic effect of 2-chlorodeoxyadenosine in patients with CLL in whom fludarabine treatment has failed.

Andre Delannoy, M.D.
Genevieve Hanique, M.D.
Augustin Ferrant, M.D.
Cliniques Universitaires Saint-Luc, 1200 Brussels, Belgium

3 References

1. 1

   Juliusson G, Elmhorn-Rosenborg A, Liliemark J. Response to 2-chlorodeoxyadenosine in patients with B-cell chronic lymphocytic leukemia resistant to fludarabine. N Engl J Med 1992;327:1056-1061
   Full Text | Web of Science | Medline

2. 2

   Cheson BD, Bennett JM, Rai KR, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group. Am J Hematol 1988;29:152-163
   CrossRef | Web of Science | Medline

3. 3

   Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2-Chlorodeoxyadenosine treatment of refractory chronic lymphocytic leukemia. Leuk Lymph 1991;5:Suppl:133-138
   CrossRef | Web of Science | Medline

To the Editor:

We have published our findings in 90 patients with refractory CLL, of whom 4 (4 percent) had complete responses and 40 (44 percent) had partial responses to 2-chlorodeoxyadenosine administered by continuous infusion and bolus regimens1. These patients were heavily pretreated but had not previously received fludarabine.

Our results differ strikingly from those of Juliusson et al. We treated 14 patients with a median of 2 courses of 2-chlorodeoxyadenosine therapy; they had previously received a median of 6 courses of fludarabine (range, 1 to 12). Their median age was 58 years, and 11 were male and 3 female; 2 patients had Rai stage II disease, 4 had stage III disease, and 8 had stage IV disease, and 5 patients had platelet counts below 50 × 10⁹ per liter. None of these 14 patients had responses, and 2 had evidence of progressive disease according to the criteria of the National Cancer Institute2. Six patients did have a sustained reduction of more than 50 percent in their absolute lymphocyte counts despite insufficient improvement in their hemoglobin concentrations or platelet counts to indicate a response. 2-Chlorodeoxyadenosine treatment was complicated by pancytopenia in two patients and by severe thrombocytopenia in three.

We strongly caution against the routine use of 2-chlorodeoxyadenosine for CLL after fludarabine has failed, given the potential hazards of severe myelosuppression and immunosuppression reported with the use of all the newer nucleosides, 2-chlorodeoxyadenosine, fludarabine, and pentostatin (deoxycoformycin)3,4. One of the four patients described in the report of Juliusson et al. died of disseminated infection with adenovirus type 1, which may have been a manifestation of these effects.

Alan Saven, M.D.
Robert H. Lemon, M.D.
Lawrence D. Piro, M.D.
Scripps Clinic and Research Foundation, La Jolla, CA 92037

4 References

1. 1

   Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2-Chlorodeoxyadenosine treatment of refractory chronic lymphocytic leukemia. Leuk Lymph 1991;5:Suppl:133-138
   CrossRef | Web of Science | Medline

2. 2

   Cheson BD, Bennett JM, Rai KR, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group. Am J Hematol 1988;29:152-163
   CrossRef | Web of Science | Medline

3. 3

   Carrera CJ, Piro LD, Saven A, et al. Restoration of lymphocyte subsets following 2-chlorodeoxyadenosine remission induction in hairy cell leukemia. Blood 1990;76:Suppl 1:260a-260a
   

4. 4

   Urba WJ, Baseler MW, Kopp WC, et al. Deoxycoformycin-induced immunosuppression in patients with hairy cell leukemia. Blood 1989;73:38-46
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We have identified two major prerequisites for responses to 2-chlorodeoxyadenosine in CLL1. First, the leukemic cells have to be drug-sensitive, a feature always manifested by a rapid decrease in the lymphocyte count after the first treatment1. This feature is probably unrelated to previous therapy, and tumor-cell elimination is as rapid during retreatment with 2-chlorodeoxyadenosine at relapse after a 2-chlorodeoxyadenosine-induced remission as it was initially (unpublished data). Sensitivity to 2-chlorodeoxyadenosine was observed in 1 of our 3 patients and in 6 of the 14 of Saven et al., which might indicate tumors with a lack of cross-resistance between fludarabine and 2-chlorodeoxyadenosine.

Unlike patients with hairy-cell leukemia, those with CLL require three to eight courses to enter complete remission1. Thus, the second prerequisite for response is the ability of normal hematopoiesis to endure repeated courses of 2-chlorodeoxyadenosine. This ability is probably related to previous chemotherapy. Presumably, the patients of Saven et al. received long-term chlorambucil therapy before fludarabine treatment, with impairment of hematopoiesis not only by leukemia but also by the previous chemotherapy.

It is noteworthy that Patient 4 in our study, who had a complete response to 2-chlorodeoxyadenosine, did not receive chlorambucil before fludarabine but did receive intermittent combination chemotherapy in high doses. However, Patient 3, who received long-term chlorambucil, had bone marrow hypoplasia due to the 2-chlorodeoxyadenosine treatment2 and died of an opportunistic infection. Of nine of our patients with CLL who had complete responses to 2-chlorodeoxyadenosine, only four had previously received chlorambucil1,3; the others had been previously treated with CHOP-like regimens (i.e., regimens incorporating cyclophosphamide, doxorubicin, vincristine, and prednisone). Alkylating agents may jeopardize stem-cell capacity. Fludarabine and 2-chlorodeoxyadenosine may reverse leukemia-induced suppression of hematopoiesis, but may not restore marrow that is terminally damaged by previous chemotherapy. Thus, failure to achieve a response with 2-chlorodeoxyadenosine is not necessarily an indication of cross-resistance between two nucleoside analogues. To determine the frequency of the cross-sensitivity that we found in a limited study population, a prospective trial of 2-chlorodeoxyadenosine in patients in whom fludarabine has failed as first-line treatment is needed.

Differences in the effects of 2-chlorodeoxyadenosine on leukemic cells should not have resulted from our use of two-hour infusions, since short-term and continuous infusions of the agent produce similar areas under the curves for levels of 2-chlorodeoxyadenosine nucleotides within CLL cells4. However, with regard to toxicity, we do not know the levels of 2-chlorodeoxyadenosine nucleotides in normal hematopoietic precursors produced by different infusion schedules.

Gunnar Juliusson, M.D., Ph.D.
Jan Liliemark, M.D., Ph.D.
Karolinska Institute at Huddinge Hospital, S-141 86 Huddinge, Sweden

4 References

1. 1

   Juliusson G, Liliemark J. High complete remission rate from 2-chloro-2'-deoxyadenosine (CdA) in previously treated patients with B-cell chronic lymphocytic leukemia: response predicted by rapid decrease of blood lymphocyte count. J Clin Oncol (in press).
   

2. 2

   Petzer AL, Bilgeri R, Zilian U, et al. Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic, erythroid, and T-lymphocytic colony growth. Blood 1991;78:2583-2587
   Web of Science | Medline

3. 3

   Juliusson G, Liliemark J. Complete remission of B-cell chronic lymphocytic leukemia after oral cladribine. Lancet 1993;341:54-54
   CrossRef | Web of Science | Medline

4. 4

   Liliemark J, Pettersson B, Juliusson G. The relationship between plasma 2-chloro-2'-deoxyadenosine (CdA) and cellular CdA nucleotides (CdAN) after intermittent and continuous I.V. infusion in patients with chronic lymphocytic leukemia. Blood 1991;78:Suppl 1:269a-269a abstract.
   

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