Blood, Vol. 89 No. 4 (February 15), 1997:
pp. 1462-1464
CORRESPONDENCE
2-Chlorodeoxyadenosine Treatment in the Sezary Syndrome
 |
LETTER |
To the Editor:
We read with interest the report by Kuzel et al1 describing the results of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF ) and the Sezary syndrome (SS). We have also treated four patients for SS. Three of them had advanced disease and were resistant to prior treatments (PUVA, chlorambucil, antilymphocyte globulin, and cyclosporin). One patient (no. 3) was enrolled to the study shortly after diagnosis. Two patients (nos. 2 and 3) had a large-cell variant of SS. The patient characteristics, stage of disease at treatment, and time from diagnosis to treatment are detailed in Table 1. 2-CdA (cladribine; Biodribin; Foundation for Development of Diagnostics and Therapy, Warsaw, Poland) was administered by 2-hour intravenous infusion at a dose of 0.14 mg/kg for 5 days. Courses were repeated at 28-day intervals. 2-CdA treatment was terminated either if there was no response after 5 courses or once prohibitive toxicity occurred. Two patients (nos. 1 and 3) received 5 cycles of therapy and one (no. 2) received 4 cycles, but in the case patient no. 4, 2-CdA treatment was reduced to two courses because of infectious complications. None of the patients achieved response. Two patients (nos. 1 and 2) experienced progression of the disease during 2-CdA treatment and eventually died. In one of these patients the cause of death was insidious bacterial sepsis. Nevertheless, in all patients we observed a decrease in lymphocyte count at least 50% from baseline (in patient no. 3 this was significant [95%]), whereas in most cases there was no change in CD4/CD8 ratio from baseline. Two patients (nos. 3 and 4) experienced grade 2 neutrocytopenia (according to the National Cancer Institute scale) and one (no. 4) experienced grade 3 thrombocytopenia. In all cases, temporal but profound, grade IV monocytopenia occurred. No patient required red blood cell transfusions. The most significant toxicities were life-threatening infectious episodes in two patients.
Our data support the view that 2-CdA has a limited activity in patients with advanced SS,1,2 although there are few patients who could benefit from this therapy. It is of interest that all of our patients received multiple courses of treatment. However, we did not achieve any clinical benefit and exposed the patients to the higher risk of immunosuppression and infectious complications.3 Likewise, all of the patients repoted by Kuzel et al1 who received more than 3 cycles of 2-CdA did not respond or achieved a very short-lasting partial response. In view of these data, we do not recommend escalating the number of 2-CdA courses in nonresponding or partially responding patients. Although the number of patients presented in our study is small, we think that the intensity of myelosuppression observed is lower in comparison to the group reported by Kuzel et al,1 especially to those treated with a 7-day continous infusion. Therefore, we think that 5-day shorter infusions at the same total dose might be an attractive alternative way of 2-CdA administration in SS. Further studies are certainly needed to select completely responding patients and explore the efficacy of 2-CdA earlier in the course of the disease.
Jan Maciej Zaucha
Krzysztof Lewandowski
Andrzej Hellmann
Department of Haematology
Hanna Pawlik
Aleksadra Siedlewicz
Department of Dermatology Medical University of Gda
sk Gdask, Poland
| |
REFERENCES |
1.
Kuzel TM,
Hurria A,
Samuelson E,
Tallman MS,
Roenigk HR,
Rademaker AW Jr,
Rosen ST:
Phase II trial of 2-Chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma.
Blood
87:906,
1996[Abstract/Free Full Text]
2.
O'Brien S,
Kurzrock R,
Duvic M,
Kantarjian H,
Stass S,
Robertson LE,
Pierce S,
Estey E,
Keating MJ:
2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders.
Blood
84:733,
1994[Abstract/Free Full Text]
3.
Cheson BD:
Infectious and immunosuppressive complication of purine analog therapy.
J Clin Oncol
13:2431,
1995[Abstract/Free Full Text]
Response
We thank Zaucha et al for the interest in our study of 2-CdA for the treatment of mycosis fungoides and the Sezary syndrome.1 They report the treatment of four patients with the Sezary syndrome with 2-CdA using 2-hour intravenous infusions at a dose of 0.14 mg/kg/d for 5 days with repeat cycles every 28 days. They continued therapy for a minimum of 5 cycles unless toxicity prevented this. No patient responded to therapy. Toxicity consisting of life-threatening infectious complications was observed in two of four patients, and myelosuppression was noted.
Several comments can be made with regard to this information. Firstly, no patient in our original report received bolus dosing of 2-CdA; rather, they received 7-day or 5-day continuous infusions. We concur with Zaucha et al that toxicity was prohibitive in the 7-day infusion cohort and that 5-day administration periods are preferred. Our experience with the 5-day bolus schedule as outlined by Liliemark and Juliusson2 is the subject of another report.3 We have not noticed dramatic differences between bolus and infusional 5-day administration schedules in terms of clinical outcomes, as measured by toxicity or response.
Secondly, the response rate in our study was 28%, suggesting that zero of four responses is within the confidence limits. Additionally, we did suggest that certain patients did less well with 2-CdA therapy. We and others have suggested that patients with large-cell variants respond poorly to a variety of treatments1,4 and have a worse prognosis at diagnosis.5 The inclusion of two patients with large-cell variants of the four reported decreased the chances of seeing a meaningful clinical response.
Finally, it is our practice to limit the number of cycles of therapy with 2-CdA to 2 in patients treated as part of a clinical trial or "off study" if minimal response is noted. The risk of significant prolonged cytopenias that may limit other therapeutic options needs to be considered in this setting, as does the risk of chronic immunosuppression. Earlier use of purine analog therapy may be more effective, but this remains to be confirmed in clinical trials. The patients treated by Zaucher et al were heavily pretreated with a median 5 prior systemic therapies.
These patients are dramatically symptomatic and desire and deserve therapy. Treatment as part of a clinical trial at a referral center is a desired goal to allow patients the opportunity to benefit from ongoing research and pharmaceutical development.
Timothy M. Kuzel
Martin S. Tallman
Department of Medicine Robert H. Lurie Cancer Center of Northwestern University Chicago, IL
| |
REFERENCES |
1.
Kuzel TM,
Hurria A,
Samuelson E,
Tallman MS,
Roenigk HR,
Rademaker AW Jr,
Rosen ST:
Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma.
Blood
87:906,
1996
2.
Liliemark J,
Juliusson G:
2-Chloro-2'-deoxyadenosine 
Clinical, biochemical and pharmacokinetic considerations.
Arch Immunol Ther Exp
42:7,
1994
3. Kong LR, Samuelson E, Rosen ST, Roenigk HH Jr, Tallman MS, Rademaker AW, Kuzel TM: 2-Chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders. Leuk Lymphoma (in press)
4.
Springer EA,
Kuzel TM,
Variakojis D,
et al:
Correlation of clinical responses with immunologic and morphologic characteristics in patients with cutaneous T-cell lymphoma treated with interferon alfa-2a.
J Am Acad Dermatol
29:42,
1993[Medline]
[Order article via Infotrieve]
5.
Schechter GP,
Sausville EA,
Fischmann AB:
Evaluation of circulating malignant cells provides prognostic information in cutaneous T-cell lymphoma.
Blood
69:841,
1987[Abstract/Free Full Text]
