International Journal of Hematology

, Volume 77, Issue 5, pp 512–517 | Cite as

Phase II Study of Cladribine (2-Chlorodeoxyadenosine) in Relapsed or Refractory Adult T-Cell Leukemia-Lymphoma

  • Kensei Tobinai
  • Naokuni Uike
  • Yoshio Saburi
  • Takaaki Chou
  • Tetsuya Etoh
  • Masato Masuda
  • Fumio Kawano
  • Masao Matsuoka
  • Hirokuni Taguchi
  • Torahiko Makino
  • Yoshinobu Asano
  • Kazuo Tamura
  • Yasuo Ohashi
Article
First Online:
Received:
Revised:
Accepted:

Abstract

Adult T-cell leukemia-lymphoma (ATL) is a retrovirus-associated T-cell malignancy with an extremely poor prognosis; the median survival time of ATL patients with the acute or lymphoma type is less than 1 year with various combination chemotherapies. Cladribine (2-chlorodeoxyadenosine; 2-CdA), a purine analog resistant to degradation by adenosine deaminase, has shown definitive clinical activity against various lymphoid malignancies, including hairy cell leukemia, indolent lymphoma, and cutaneous T-cell lymphoma. An in vitro study showed the sensitivity of T-lymphoblastoid cell lines to cladribine, and a preceding Japanese phase I study of cladribine showed that 1 refractory patient with ATL achieved an objective response. To evaluate the therapeutic efficacy of cladribine in treating ATL, we conducted a multicenter phase II study. The plan was to administer cladribine to 30 ATL patients as 0.09 mg/kg per day by 7-day continuous intravenous infusion every 4 weeks for up to 3 courses. Before the planned interim analysis, 16 patients with relapsed or refractory ATL were enrolled, 15 of whom were eligible. Only 1 of the 15 eligible patients showed an objective response (overall response rate, 7%; 90% confidence interval, 0% to 28%), and 11 patients (73%) showed progressive disease, mostly during the first course of treatment. Because the upper limit of the 90% confidence interval of the overall response rate did not reach 30% in the interim analysis, the Independent Monitoring Committee advised us to discontinue patient enrollment. In conclusion, cladribine is not worthy of further investigation for the treatment of ATL.

Key words

Cladribine 2-Chlorodeoxyadenosine 2-CdA Adult T-cell leukemia-lymphoma ATL Phase II study 
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References

  1. 1.
    Uchiyama T, Yodoi J, Sagawa K, et al. Adult T-cell leukemia: clini- cal and hematologic features of 16 cases.Blood. 1977;50:481–492.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Yoshida M, Miyoshi I, Hinuma Y. Isolation and characterization of retrovirus from cell lines of human adult T cell leukemia and its implication in the disease.Proc NatlAcad Sci USA. 1982;79:2031–2035.CrossRefGoogle Scholar
  3. 3.
    Shimoyama M. Diagnostic criteria and classification of clinical sub- types of adult T-cell leukaemia-lymphoma: a report from the Lym- phoma Study Group (1984-87).Br J Haematol. 1991;79:428–437.CrossRefGoogle Scholar
  4. 4.
    Tobinai K. Adult T-cell leukemia-lymphoma. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE, eds.Clinical Oncology. 2nd ed. New York, NY: Churchill Livingstone; 2000:2748–2768.Google Scholar
  5. 5.
    Shimoyama M, Ota K, Kikuchi M, et al. Chemotherapeutic results and prognostic factors of patients with advanced non-Hodgkin’s lymphoma treated with VEPA or VEPA-M.J Clin Oncol. 1988;6:128–141.CrossRefGoogle Scholar
  6. 6.
    Shimoyama M, Ota K, Kikuchi M, et al. Major prognostic factors of adult patients with advanced T-cell Iymphoma/leukemia.J Clin Oncol. 1988;6:1088–1097.CrossRefGoogle Scholar
  7. 7.
    Tobinai K, Shimoyama M, Minato K, et al. Japan Clinical Oncology Group phase II trial of second-generation “LSG4 protocol” in aggressive T- and B-lymphoma: a new predictive model for T- and B-lymphoma [abstract].Proc Am Soc Clin Oncol. 1994;13:378.Google Scholar
  8. 8.
    Tobinai K, Shimoyama M, Inoue S, et al. Phase I study of YK-176 (2’-deoxycoformycin) in patients with adult T-cell leukemia- lymphoma.Jpn J Clin Oncol. 1992;22:164–171.PubMedGoogle Scholar
  9. 9.
    ShimoyamaM. Chemotherapy of ATL. In: TakatsukiK, ed.Adult T-cell Leukaemia. Oxford, UK: Oxford University Press; 1994:221.Google Scholar
  10. 10.
    Tsukasaki K, Tobinai K, Shimoyama M, et al. Deoxycoformycin- containing combination chemotherapy for adult T-cell leukemia- lymphoma: Japan Clinical Oncology Group Study (JCOG9109).Int J Hematol. 2003;77:164–170.CrossRefGoogle Scholar
  11. 11.
    Carson DA, Kaye J, Seegmiller JE. Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphory- lase deficiency: possible role of nucleoside kinase(s).Proc Natl AcadSci USA. 1977;77:5677–5681.CrossRefGoogle Scholar
  12. 12.
    Carson DA,Wasson DB, Kaye J, et al. Deoxycytidine kinase-medi- ated toxicity of deoxyadenosine analogs toward malignant human lymphoblasts in vitro and toward murine L1210 leukemia in vivo.Proc Natl Acad Sci USA. 1980;77:6865–6869.CrossRefGoogle Scholar
  13. 13.
    Beutler E. Cladribine (2-chlorodeoxyadenosine).Lancet. 1992;340:952–956.CrossRefGoogle Scholar
  14. 14.
    Piro LD, Carrera CJ, Carson DA, Beutler E. Lasting remissions in hairy-cell leukemia induced by single infusion of 2-chlorodeoxyadenosine.N Engl J Med. 1990;322:1117–1121.CrossRefGoogle Scholar
  15. 15.
    Tallman MS, Hakimian D, Variakojis D, et al. A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia.Blood. 1992;80:2203–2209.PubMedGoogle Scholar
  16. 16.
    Juliusson G, Liliemark J. High complete remission rate of 2-chloro-2’-deoxyadenosine in previously treated patients with B-cell chronic lymphocytic leukemia: response predicted by rapid decrease of blood lymphocyte count.J Clin Oncol. 1993;11:679–689.CrossRefGoogle Scholar
  17. 17.
    Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia.J Clin Oncol. 1995;13:570–574.CrossRefGoogle Scholar
  18. 18.
    Barton K, Larson RA, O’Brien S, Ratain MJ. Rapid response of B-cell prolymphocytic leukemia to 2-chlorodeoxyadenosine [let- ter].J Clin Oncol. 1992;10:1821.CrossRefGoogle Scholar
  19. 19.
    Kay AC, Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2-Chlorodeoxyadenosine treatment of low-grade lymphomas.J Clin Oncol. 1992;10:371–377.CrossRefGoogle Scholar
  20. 20.
    Hoffman M,Tallman MS, Hakimian D, et al. 2-Chlorodeoxyadenosine is an active salvage therapy in advanced non-Hodgkin’s lymphoma.J Clin Oncol. 1994;12:788–792.CrossRefGoogle Scholar
  21. 21.
    Saven A, Emanuele S, Kosty M, Koziol J, Ellison D, Piro L. 2-Chlorodeoxyadenosine activity in patients with untreated, indo- lent non-Hodgkin’s lymphoma.Blood. 1995;86:1710–1716.PubMedGoogle Scholar
  22. 22.
    Seto S, Carrera CJ, Kubota M, Wasson DB, Carson DA. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondi- viding human lymphocytes.J Clin Invest. 1985;75:377–383.CrossRefGoogle Scholar
  23. 23.
    Saven A, Carrera CJ, Carson DA, Beutler E, Piro LD. 2-Chlorodeoxyadenosine: an active agent in the treatment of cuta- neous T-cell lymphoma.Blood. 1992;80:587–592.PubMedGoogle Scholar
  24. 24.
    O’Brien S, Kurzrock R, Duvic M, et al. 2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders.Blood. 1994;84:733–738.PubMedGoogle Scholar
  25. 25.
    Kuzel TM, Hurria A, Samuelson E, et al. Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lym- phoma.Blood. 1996;87:906–911.PubMedGoogle Scholar
  26. 26.
    Tobinai K, Ogura M, Hotta T, et al. Phase I study of cladribine (2-chlorodeoxyadenosine) in lymphoid malignancies.Jpn J Clin Oncol. 1997;27:146–153.CrossRefGoogle Scholar
  27. 27.
    Uike N, Choi I, Tokoro A, et al. Adult T-cell leukemia-lymphoma successfully treated with 2-chlorodeoxyadenosine.Intern Med. 1998;37:411–413.CrossRefGoogle Scholar
  28. 28.
    Simon R. Optimal two-stage designs for phase II clinical trials.Control Clin Trials. 1989;10:1–10.CrossRefGoogle Scholar
  29. 29.
    Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group.Am J Clin Oncol. 1982;5:649–655.CrossRefGoogle Scholar
  30. 30.
    Tobinai K, Kohno A, Shimada Y, et al. Toxicity grading criteria of the Japan Clinical Oncology Group (JCOG).Jpn J Clin Oncol. 1993;23:250–257.CrossRefGoogle Scholar
  31. 31.
    World Health Organization.WHO Handbook for Reporting Results of Cancer Treatment. Geneva, Switzerland: World Health Organization; 1979. Publication No. 48.Google Scholar
  32. 32.
    Yamada Y, Tomonaga M, Fukuda H, et al. A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia- lymphoma: Japan Clinical Oncology Group Study 9303.Br J Haematol. 2001;113:375–382.CrossRefGoogle Scholar
  33. 33.
    Taguchi H, Kinoshita K, Takatsuki K, et al. An intensive chemo- therapy of adult T-cell leukemia/lymphoma: CHOP followed by etoposide, vindesine, ranimustine, and mitoxantrone with granulo- cyte colony-stimulating factor support.J Acquir Immune Defic Syndr Hum Retrovirol. 1996;12:182–186.CrossRefGoogle Scholar
  34. 34.
    Sparano JA, Wiernik PH, Strack M, et al. Infusional cyclophos- phamide, doxorubicin, and etoposide in human immunodefi- ciency virus- and human T-cell leukemia virus type I-related non- Hodgkin’s lymphoma: a highly active regimen.Blood. 1993;81:2810–2815.PubMedGoogle Scholar
  35. 35.
    Waldmann TA, White JD, Goldman CK, et al. The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotropic virus I-induced adult T-cell leukemia.Blood. 1993;82:1701–1712.PubMedGoogle Scholar
  36. 36.
    Waldmann TA, White JD, Carrasquillo JA, et al. Radioimmunotherapy of interleukin-2Rα-expressing adult T-cell leukemia with yttrium-90-labeled anti-Tac.Blood. 1995;86:4063–4075.PubMedGoogle Scholar
  37. 37.
    Zhang M, Yao Z, Garmestani K, et al. Pretargeting radioim- munotherapy of a murine model of adult T-cell leukemia with the α-emitting radionuclide, bismuth 213.Blood. 2002;100:208–216.CrossRefGoogle Scholar
  38. 38.
    Ishitsuka K, Hanada S, Suzuki S, et al. Arsenic trioxide inhibits growth of human T-cell leukaemia virus type I infected T-cell lines more effectively than retinoic acids.Br J Haematol. 1998;103:721–728.CrossRefGoogle Scholar
  39. 39.
    Bazarbachi A, El-Sabban ME, Nasr R, et al. Arsenic trioxide and interferon-alpha synergize to induce cell cycle arrest and apoptosis in human T-cell lymphotropic virus type I-transformed cells.Blood. 1999;93:278–283.PubMedGoogle Scholar
  40. 40.
    Utsunomiya A, Miyazaki Y, Takatsuka Y, et al. Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation.Bone Marrow Transplant. 2001;27:15–20.CrossRefGoogle Scholar
  41. 41.
    Abe Y, Yashiki S, Choi I, et al. Eradication of virus-infected T-cells in a case of adult T-cell leukemia/lymphoma by nonmyeloablative peripheral blood stem cell transplantation with conditioning con- sisting of low-dose total body irradiation and pentostatin.Int J Hematol. 2002;76:91–93.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  • Kensei Tobinai
    • 1
  • Naokuni Uike
    • 2
  • Yoshio Saburi
    • 3
  • Takaaki Chou
    • 4
  • Tetsuya Etoh
    • 5
  • Masato Masuda
    • 6
  • Fumio Kawano
    • 7
  • Masao Matsuoka
    • 8
  • Hirokuni Taguchi
    • 9
  • Torahiko Makino
    • 10
  • Yoshinobu Asano
    • 11
  • Kazuo Tamura
    • 12
  • Yasuo Ohashi
    • 13
  1. 1.Hematology DivisionNational Cancer Center HospitalTokyoJapan
  2. 2.National Kyushu Cancer CenterFukuoka
  3. 3.Oita Prefectural HospitalOita
  4. 4.Niigata Cancer CenterNiigata
  5. 5.Hara Sanshin HospitalFukuoka
  6. 6.University of the RyukyusOkinawa
  7. 7.Kumamoto National HospitalKumamoto
  8. 8.Kumamoto UniversityKumamoto
  9. 9.Kochi Medical SchoolNangoku
  10. 10.Imamura Bun- in HospitalKagoshima
  11. 11.Kyushu UniversityFukuoka
  12. 12.Fukuoka UniversityFukuoka
  13. 13.University of TokyoTokyoJapan

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