Correspondence

Interferon Alfa and Zidovudine in Adult T-Cell Leukemia–Lymphoma

N Engl J Med 1995; 333:1285-1286November 9, 1995

Article

To the Editor:

Gill et al. (June 29 issue)1 report the encouraging results of a trial in which interferon alfa and zidovudine were combined for the treatment of adult T-cell leukemia–lymphoma. The response to this treatment was impressive, and the toxicity levels were acceptable. These results may be a blessing for patients with adult T-cell leukemia–lymphoma in Japan, where more than 700 new cases are diagnosed each year among the 1.2 million carriers of the human T-cell lymphotropic virus type I.2 However, two points are not clear.

First, is the combination of interferon alfa and zidovudine essential? It has already been reported that some patients with adult T-cell leukemia–lymphoma have responses to interferon alone,3 as indicated in the report by Gill et al. The good response rate in their trial may be attributable to the selection of patients or the small sample.

Second, what was the median survival of the previously untreated patients who received this combination of drugs? Although the authors do not specify median survival, on the basis of their data, it appears to have been less than five months, which is worse than the survival in our trials, involving a total of 157 patients. In our studies, the survival for patients undergoing first-generation combination chemotherapy, second-generation combination chemotherapy, and deoxycoformycin-containing combination chemotherapy was 7.5, 8.3, and 7.4 months, respectively.4,5 Furthermore, the rate of complete remission associated with the use of interferon alfa and zidovudine in previously untreated patients (25 percent, or 3 of 12 patients) is not superior to the rates in our three groups of patients (28 percent, 15 of 54; 42 percent, 18 of 43; and 28 percent, 17 of 60, respectively).4,5 At present, we hesitate to accept the combination of interferon alfa and zidovudine as first-line chemotherapy in patients with newly diagnosed adult T-cell leukemia–lymphoma.

Alternatively, as the authors note, the combination may be one of the promising treatments for patients who do not have responses to cytotoxic chemotherapy, because four of the seven patients with no responses to prior cytotoxic therapy had major responses to the combination of interferon alfa and zidovudine, including clinical remission in two patients. The optimal role of this combination treatment should be evaluated further in large-scale trials.

Kensei Tobinai, M.D.
Yukio Kobayashi, M.D.
National Cancer Center Hospital, Chuo-ku, Tokyo 104, Japan

Masanori Shimoyama, M.D.
National Nagoya Hospital, Naka-ku, Nagoya 460, Japan

for the Lymphoma Study Group of the Japan Clinical Oncology Group

5 References

1
Gill PS, Harrington W Jr, Kaplan MH, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995;332:1744-1748
Full Text | Web of Science | Medline

2
Tajima K, T- and B-cell Malignancy Study Group. The 4th nation-wide study of adult T-cell leukemia/lymphoma (ATL) in Japan: estimates of risk of ATL and its geographical and clinical features. Int J Cancer 1990;45:237-243
CrossRef | Web of Science | Medline

3
Ichimaru M, Kamihira S, Moriuchi Y, et al. Clinical study on the effect of natural α-interferon (HLBI) in the treatment of adult T-cell leukemia. Jpn J Cancer Chemother 1988;15:2975-2981
Medline

4
Shimoyama M. Chemotherapy of ATL. In: Takatsuki K, ed. Adult T-cell leukemia. Oxford, England: Oxford Medical Publications, 1994:221-37.

5
Tobinai K, Shimoyama M, Tajima K, et al. Deoxycoformycin (DCF)-containing combination chemotherapy for adult T-cell leukemia-lymphoma (ATL): Japan Clinical Oncology Group (JCOG) Study #9109. Prog Proc Am Soc Clin Oncol 1995;14:390-390 abstract.

To the Editor:

In patients with adult T-cell leukemia–lymphoma, the response to a combination of interferon alfa and zidovudine1-3 may be lymphoid-specific rather than T-cell–specific, at least in cell culture. Immortalization of human umbilical-cord B cells by Epstein–Barr virus (EBV) in cell culture was inhibited by 74 percent with a combination of interferon alfa (1 U per milliliter) and zidovudine (0.1 mM); these agents had a strong synergistic effect (combination index, 0.116; values of less than 1 indicate synergy).4 Zidovudine inhibits replication of EBV,5 but the antiviral effect probably did not contribute to the cellular inhibitory effect, since the EBV-immortalized cells were latently infected. These results suggest that the effect of the combination was neither virus-specific nor T-cell–specific.

Even more striking inhibitory effects on EBV-induced cell immortalization were produced by a combination of very low doses (0.05 to 1 U per milliliter) of interferon alfa and interferon gamma, which yielded combination indexes of 0.01 to 0.02 — approximately 10 times better than the index for interferon alfa plus zidovudine.4 It may be worth determining whether these results in cell culture with what appear to be nontoxic levels of interferon alfa and interferon gamma can be applied to the treatment of adult T-cell leukemia–lymphoma and EBV-induced lymphoproliferative syndromes.

Joseph S. Pagano, M.D.
University of North Carolina School of Medicine, Chapel Hill, NC 27599-7295

5 References

1
Gill PS, Harrington W Jr, Kaplan MH, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med 1995;332:1744-1748
Full Text | Web of Science | Medline

2
Hermine O, Bouscary D, Gessain A, et al. Treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa. N Engl J Med 1995;332:1749-1751
Full Text | Web of Science | Medline

3
Gallo RC. A surprising advance in the treatment of viral leukemia. N Engl J Med 1995;332:1783-1785
Full Text | Web of Science | Medline

4
Lin JC, Zhang ZX, Chou TC, Sim I, Pagano JS. Synergistic inhibition of Epstein-Barr virus: transformation of B lymphocytes by α and γ interferon and by 3'-azido-3'-deoxythymidine. J Infect Dis 1989;159:248-254
CrossRef | Web of Science | Medline

5
Lin JC, Zhang ZX, Smith MC, Biron K, Pagano JS. Anti-human immunodeficiency virus agent 3'-azido-3'-deoxythymidine inhibits replication of Epstein-Barr virus. Antimicrob Agents Chemother 1988;32:265-267
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Interferon alfa has been used alone in patients with acute and lymphomatous types of adult T-cell leukemia–lymphoma in a number of trials, and the rates of overall and complete responses have been less than 20 percent and less than 5 percent, respectively.1,2 The response rates of 58 percent in our series and 100 percent in the series of five patients described by Hermine et al.3 in the same issue suggest that the combination of zidovudine and interferon alfa is more active than interferon alfa alone. Notably, the response rate was high in our series despite poor prognostic features in all 19 patients.

The median survival in 12 of the previously untreated patients in our series was 4.8 months. Three patients have survived longer than 12 months. All five patients described by Hermine et al. have lived for 12 months or more.3 In comparison, the median survival of 7.4 months, reported by Tobinai et al.,4 with the most active chemotherapy regimen is not significantly different from that with zidovudine and interferon alfa. It should be noted that nearly half the patients in the series described by Tobinai et al. had lymphoma and chronic types of adult T-cell leukemia–lymphoma, which are associated with a substantially better survival than the acute form. Survival is also affected by various other factors, including age, performance status, and serum lactate dehydrogenase and calcium levels. For these reasons, we proposed that randomized trials be conducted to compare the best cytotoxic chemotherapy regimen with the combination of zidovudine and interferon alfa.

Lastly, no effective therapy is currently available for patients who have not had responses to cytotoxic chemotherapy. Among the seven patients in our study who had not had responses to prior therapy, the rates of overall and complete responses were similar to those among the previously untreated patients. Zidovudine and interferon alfa should therefore also be studied in large series of patients who have not had responses to conventional therapy.

Parkash S. Gill, M.D.
University of Southern California School of Medicine, Los Angeles, CA 90033

William Harrington, Jr., M.D.
University of Miami, Miami, FL 33101

Alexandra M. Levine, M.D.
University of Southern California School of Medicine, Los Angeles, CA 90033

4 References

1
Kamihira S, Soda H, Kinoshita K, Ichimaru M. Effect of human lymphoblast interferon in adult T-cell leukemia and non-Hodgkin's lymphoma. Jpn J Cancer Chemother 1983;10:2188-2193
Medline

2
Ichimaru M, Kamihira S, Moriuchi Y, et al. Clinical study of the effect of natural α-interferon (HLBI) in the treatment of adult T-cell leukemia. Jpn J Cancer Chemother 1988;15:2975-2981
Medline

3
Hermine O, Bouscary D, Gessain A, et al. Treatment of adult T-cell leukemia-lymphoma with zidovudine and interferon alfa. N Engl J Med 1995;332:1749-1751
Full Text | Web of Science | Medline

4
Tobinai K, Shimoyama M, Tajima K, et al. Deoxycoformycin (DCF)-containing combination chemotherapy for adult T-cell leukemia-lymphoma (ATL): Japan Clinical Oncology Group (JCOG) Study #9109. Prog Proc Am Soc Clin Oncol 1995;14:390-390 abstract.

Citing Articles (5)

Citing Articles

1
Kunihiro Tsukasaki, Kensei Tobinai. (2012) Clinical Trials and Treatment of ATL. Leukemia Research and Treatment 2012, 1-12
CrossRef
2
K. Tsukasaki, K. Tobinai, T. Hotta, M. Shimoyama. (2011) Lymphoma Study Group of JCOG. Japanese Journal of Clinical Oncology
CrossRef
3
Christophe Nicot. (2005) Current views in HTLV-I-associated adult T-cell leukemia/lymphoma. American Journal of Hematology 78:3, 232-239
CrossRef
4
K. Tobinai. (2004) Clinical Trials for Malignant Lymphoma in Japan. Japanese Journal of Clinical Oncology 34:7, 369-378
CrossRef
5
Styliani I Kokoris, Marina P Siakantaris, Flora N Kontopidou, Marie-Christine Kyrtsonis, Athanassios Tsakris, Nikolaos Spanakis, Konstantinos Anargyrou, Theodoros P Vassilakopoulos, Nora-Athina Viniou, Penelope Korkolopoulou, Aglaia D Dimitrakopoulou, Nikolaos Legakis, Gerassimos A Pangalis. (2004) Adult T-Cell Leukemia/Lymphoma (ATLL): Report of Two Fully Documented Hellenic Patients. Leukemia & Lymphoma 45:4, 715-721
CrossRef