Abstract
Recently, arsenic trioxide (ATO) has been proved to induce complete remission (CR) at a high rate in patients with acute promyelocytic leukemia (APL).We prospectively investigated the safety and efficacy of ATO therapy in patients with relapsed and refractory APL and examined the duration of CR and the postremission therapies. Initially, 0.15 mg/kg ATO was administered until bone marrow remission to a maximum of 60 days. After the patient achieved CR, 1 additional ATO course at the same dosage was administered for 25 days. Of 34 patients, 31 (91%) achieved CR. PML-RARα messenger RNA was not detected in the bone marrow of 18 (72%) of the 25 patients evaluated by reverse transcriptase—polymerase chain reaction analysis. At a median follow-up of 30 months, the estimated 2-year overall survival rate was 56%, and the estimated 2-year event-free survival rate was 17%. During the ATO therapy, QTc prolongation was observed in most cases. Fifteen patients developed ventricular tachycardia, and 1 of them showed torsades de pointes. Other adverse events were nausea, water retention, APL differentiation syndrome, skin eruption, liver dysfunction, and peripheral neuropathy, all of which were quite tolerable. ATO therapy was remarkably effective for relapsed APL; however, postremission therapies were necessary to maintain a durable remission.
Article PDF
Similar content being viewed by others
References
de The H, Chomienne C, Lanotte M, Degos L, Dejean A.The t(15; 17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990;347:558–561.
Kakizuka A, Miller WH Jr, Umesono K, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991;66:663–674.
Huang ME,Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72: 567–572.
Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia, I: clinical results. Blood. 1990;76:1704–1709.
Ohno R,Yoshida H, Fukutani H, et al. Multi-institutional study of all-trans-retinoic acid as a differentiation therapy of refractory acute promyelocytic leukemia: Leukaemia Study Group of the Ministry of Health and Welfare. Leukemia. 1993;7:1722–1727.
Kanamaru A, Takemoto Y, Tanimoto M, et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia: Japan Adult Leukemia Study Group. Blood. 1995;85: 1202–1206.
Ohno R, Ohnishi K,Takeshita A, et al. All-trans retinoic acid therapy in relapsed/refractory or newly diagnosed acute promyelocytic leukemia (APL) in Japan. Leukemia. 1994;8(suppl 3):S64-S69.
Asou N, Adachi K,Tamura J, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with alltrans retinoic acid and chemotherapy: Japan Adult Leukemia Study Group. J Clin Oncol. 1998;16:78–85.
Nabhan C, Mehta J, Tallman MS. The role of bone marrow transplantation in acute promyelocytic leukemia. Bone Marrow Transplant. 2001;28:219–226.
Sun H, Ma L, Hu X, Zhang T. Treatment of acute promyelocytic leukemia with arsenic trioxide [in Chinese]. Chin Combinat West Chin Med. 1992;12:170–171.
Zhang P, Wang S, Longhu H. Treatment of acute promyelocytic leukemia with intravenous arsenic trioxide [in Chinese]. Chin J Hematol. 1996;17:58–60.
Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL), II: clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89: 3354–3360.
Niu C,Yan H,Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315–3324.
Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341–1348.
Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–3860.
Ohnishi K, Yoshida H, Shigeno K, et al. Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia: need for careful electrocardiogram monitoring. Leukemia. 2002;16:617–622.
World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Ferney-Voltaire, France:World Medical Association; 1964.
Shigeno K, Nakamura S, Naito K, et al. Arsenic trioxide therapy for relapsed or refractory Japanese patients with acute promyelocytic leukemia [abstract]. Blood. 2002;100:264b.
Jaffe ES, Harris NL, Stein H,Vardiman JW, eds. WHO Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:75–107.
Tallman MS, Andersen JW, Schiffer CA, et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood. 2000;95:90–95.
Ohnishi K, Yoshida H, Shigeno K, et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med. 2000; 133:881–885.
Kaplan EL, Meier P. Non-parametric estimation from incomplete observation. J Am Stat Assoc. 1958;53:457–481.
Tobita T,Takeshita A, Kitamura K, et al.Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997;90:967–973.
Kitamura K, Kiyoi H, Yoshida H, et al. New retinoids and arsenic compounds for the treatment of refractory acute promyelocytic leukemia: clinical and basic studies for the next generation. Cancer Chemother Pharmacol. 1997;40(suppl):S36-S41.
de Botton S, Fawaz A, Chevret S, et al.Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European Acute Promyelocytic Leukaemia Group. J Clin Oncol. 2005;23:120–126.
Au WY, Chim JC, Lie AK, et al. Treatment of relapsed acute promyelocytic leukemia by arsenic-based strategies without hematopoietic stem cell transplantation in Hong Kong: a sevenyear experience [abstract]. Blood. 2004;104:116a.
Waxman S, Anderson KC. History of the development of arsenic derivatives in cancer therapy. Oncologist. 2001;6(suppl 2):3–10.
Wassmann S, Nickenig G, Bohm M. Long QT syndrome and torsade de pointes in a patient receiving fluconazole. Ann Intern Med. 1999;131:797.
Tanvetyanon T, Nand S. Herpes zoster during treatment with arsenic trioxide. Ann Hematol. 2004;83:198–200.
Lo Coco F, Romano A, Mengarelli A, et al. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia. 2003;17:1930–1933.
Author information
Authors and Affiliations
About this article
Cite this article
Shigeno, K., Naito, K., Sahara, N. et al. Arsenic Trioxide Therapy in Relapsed or Refractory Japanese Patients with Acute Promyelocytic Leukemia: Updated Outcomes of the Phase II Study and Postremission Therapies. Int J Hematol 82, 224–229 (2005). https://doi.org/10.1532/IJH97.05044
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1532/IJH97.05044