PDF icon Download PDF
Dtsch Med Wochenschr 2007; 132(7): 330-336
DOI: 10.1055/s-2007-959329
Übersicht | Review article
Onkologie
© Georg Thieme Verlag KG Stuttgart · New York

Arsentrioxid: „ein erfolgreiches Gift” bei Patienten mit akuter Promyelozytenleukämie

Arsenic trioxide: a „successful poison” in patients with acute promyelocytic leukemiaE. Lengfelder1 , B. Schultheis1 , T. Büchner2 , R. Hehlmann1
  • 1III. Medizinische Universitätsklinik Mannheim, Universität Heidelberg
  • 2Medizinische Universitätsklinik A, Universität Münster
Further Information

Publication History

eingereicht: 13.9.2006

akzeptiert: 17.1.2007

Publication Date:
07 February 2007 (online)

Also available ateRef
   Permissions and Reprints
Preview

Zusammenfassung

Die Wirksamkeit von Arsenderivaten bei Neoplasien beruht auf komplexen Mechanismen. Bei der Therapie der akuten Promyelozytenleukämie (APL) steht ein dualer, zur Differenzierung und Apoptose der Blasten führender Effekt im Vordergrund.

Diese Zusammenfassung gibt einen Überblick über Aspekte der Pharmakologie, klinische Effizienz und unerwünschte Effekte von Arsentrioxid (ATO) bei APL. In 17 internationalen Studien zur Primär- und Rezidivtherapie mit ATO wurden insgesamt 565 Patienten eingeschlossen. Von den Patienten mit rezidivierter APL (n = 266) erreichten insgesamt 85,7 % eine Remission bei guter Verträglichkeit von ATO. Das Überleben nach 2 Jahren lag bei 50 bis 77 %. Bei neu diagnostizierter APL (n = 299) wurden Remissionsraten zwischen 73 und 95 % erreicht. Blutungskomplikationen, überwiegend zerebral, umfassten 66 % der Frühtodesfälle und waren die häufigste Todesursache. Die häufigste unerwünschte Begleiterscheinung von ATO war das APL-Differenzierungssyndrom bei bis zu 25 % der Patienten. Bei kurzen Beobachtungszeiten sind Langzeiteffekte noch nicht einschätzbar.

ATO erweist sich als hocheffizient in der Behandlung der APL. Es ist für die rezidivierte und refraktäre APL zugelassen.

Summary

he mechanism of action of arsenic derivates in neoplasitic disease is complex. Cell differentiation and apoptosis are of utmost importance in the therapy of acute promyelocytic leukemia (APL). This review considers essential aspects of the pharmacology, clinical efficacy and adverse effects of arsenic trioxide (ATO) in APL. So far ATO treatment has been investigated in 17 international studies encompassing 565 patients with either initially diagnosed or relapsed APL. 85.7% of patients with relapsed APL (n=266) had a remission and ATO was well tolerated. The overall survival after two years ranged from 50 to 77%. In the initial therapy of APL (n=299), complete remission was achieved in 73 to 95% of patients. The most frequent cause of death (66% of early deaths) was bleeding complications, mostly cerebral bleedings. The most common adverse effect of ATO (in up to 25% of patients) was the APL-differentiation syndrome. Because of the short follow-up periods, long-term effects cannot as yet be evaluated. Arsenic trioxide (ATO) is highly efficacious in the treatment of APL. Its use has been approved for relapsed and refractory APL.

Schlüsselwörter

Arsentrioxid - Promyelozytenleukämie

Key words

arsenic toxide - promyelocytic leukemia

Literatur

  • 1 Au W Y, Chim C S, Lie A K, Liang R, Kwong Y L. Combined arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia recurring from previous relapses successfully treated using arsenic trioxide.  Br J Haematol. 2002;  117 130-132
    Search in Google Scholar
  • 2 Bachleitner-Hofmann T, Gisslinger B, Grumbeck E, Gisslinger H. Arsenic trioxide and ascorbic acid: synergy with potential implications for the treatment of acute myeloid leukaemia?.  Br J Haematol. 2001;  112 783-786
    Search in Google Scholar
  • 3 Camacho L H, Soignet S L, Chanel S. et al . Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide.  J Clin Oncol. 2000;  18 2620-2625
    Search in Google Scholar
  • 4 Carmosino I, Latagliata R, Avvisati G. et al . Arsenic trioxide in the treatment of advanced acute promyelocytic leukemia.  Haematologica. 2004;  89 615-617
    Search in Google Scholar
  • 5 Chen G Q, Shi X G, Tang W. et al . Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells.  Blood. 1997;  89 3345-3353
    Search in Google Scholar
  • 6 Chou W C, Hawkins A L, Barrett J F, Griffin C A, Dang C V. Arsenic inhibition of telomerase transcription leads to genetic instability.  J Clin Invest. 2001;  108 1541-1547
    Search in Google Scholar
  • 7 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 leukemia group.  J Clin Oncol. 2005;  23 120-126
    Search in Google Scholar
  • 8 Degos L, Dombret H, Chomienne C. et al . All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia.  Blood. 1995;  85 2643-2653
    Search in Google Scholar
  • 9 Douer D, Hu W, Giralt S, Lill M, DiPersio J. Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation.  Oncologist. 2003;  8 132-140
    Search in Google Scholar
  • 10 Douer D, Tallman M S. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies.  J Clin Oncol. 2005;  23 2396-2410
    Search in Google Scholar
  • 11 Doyle A C. Notes of a case of leukocythaemia.  Lancet. 1882;  119 490
    Search in Google Scholar
  • 12 Estey E, Garcia-Manero G, Ferrajoli A. et al . Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia.  Blood. 2006;  107 3469-3473
    Search in Google Scholar
  • 13 Forkner C E, Scott T F. Arsenic as a therapeutic agent in chronic myelogenous leukemia.  JAMA. 1931;  97 3-5
    Search in Google Scholar
  • 14 Frankel S R, Eardley A, Lauwers G, Weiss M, Warrell R P. The „retinoic acid syndrome” in acute promyelocytic leukemia.  Ann Intern Med. 1992;  117 292-296
    Search in Google Scholar
  • 15 George B, Mathews V, Poonkuzhali B, Shaji R V, Srivastava A, Chandy M. Treatment of children with newly diagnosed acute promyelocytic leukemia with arsenic trioxide: a single center experience.  Leukemia. 2004;  18 1587-1590
    Search in Google Scholar
  • 16 Ghavamzadeh A, Alimoghaddam K, Ghaffari S H. et al . Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy.  Ann Oncol. 2006;  17 131-134
    Search in Google Scholar
  • 17 Helwig A, Klemm M, Schuttig R. et al . Arsenic-induced APL differentiation in cerebrospinal fluid.  Leuk Res. 2006;  , Epub ahead of print
    Search in Google Scholar
  • 18 Jing Y, Wang L, Xia L. et al . Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo.  Blood. 2001;  97 264-269
    Search in Google Scholar
  • 19 Kai T, Kimura H, Shiga Y, Ogawa K, Sato H, Maruyama Y. Recurrent extramedullary relapse of acute promyelocytic leukemia after allogeneic stem cell transplantation: successful treatment by arsenic trioxide in combination with local radiotherapy.  Int J Hematol. 2006;  83 337-340
    Search in Google Scholar
  • 20 Kwong Y L, Au W Y, Chim C S, Pang A, Suen C, Liang R. Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study.  Am J Hematol. 2001;  66 274-279
    Search in Google Scholar
  • 21 Lazo G, Kantarjian H, Estey E, Thomas D, O’Brien S, Cortes J. Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M. D. Anderson experience.  Cancer. 2003;  97 2218-2224
    Search in Google Scholar
  • 22 Lengfelder E, Gnad U, Büchner T, Hehlmann R. Treatment of relapsed acute promyelocytic leukemia.  Onkologie. 2003;  26 373-379
    Search in Google Scholar
  • 23 Lengfelder E, Hehlmann R, Büchner T. Aktuelle Therapiekonzepte bei akuter Promyelozytenleukämie.  Dtsch Med Wochenschr. 2001;  126 1073-1079
    Search in Google Scholar
  • 24 Lengfelder E, Saussele S, Weisser A, Büchner T, Hehlmann R. Treatment concepts of acute promyelocytic leukemia.  Crit Rev Oncol Hematol. 2005;  56 261-274
    Search in Google Scholar
  • 25 Leoni F, Gianfaldoni G, Annunziata M. et al . Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation.  Haematologica. 2002;  87 485-489
    Search in Google Scholar
  • 26 Lu D P, Qiu J Y, Jiang B. et al . Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report.  Blood. 2002;  99 3136-3143
    Search in Google Scholar
  • 27 Mathews V, George B, Lakshmi K M. et al . Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity.  Blood. 2006;  107 2627-2632
    Search in Google Scholar
  • 28 Miller W H, Schipper H M, Lee J S, Singer J, Waxman S. Mechanisms of action of arsenic trioxide.  Cancer Res. 2002;  62 3893-3903
    Search in Google Scholar
  • 29 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
    Search in Google Scholar
  • 30 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
    Search in Google Scholar
  • 31 Raffoux E, Rousselot P, Poupon J. et al . Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.  J Clin Oncol. 2003;  21 2326-2334
    Search in Google Scholar
  • 32 Roboz G J, Dias S, Lam G. et al . Arsenic trioxide induces dose- and time-dependent apoptosis of endothelium and may exert an antileukemic effect via inhibition of angiogenesis.  Blood. 2000;  96 1525-1530
    Search in Google Scholar
  • 33 Sanz M A, Arcese W, de la Rubia J. et al . Stem cell transplantation for acute promyelocytic leukemia in the ATRA era: A survey of the European Blood and Marrow Transplantation Group.  Blood. 2000;  96 522a
    Search in Google Scholar
  • 34 Sanz M A, Fenaux P, LoCoco F. Arsenic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence.  Haematologica. 2005;  90 1231-1235
    Search in Google Scholar
  • 35 Shen Y, Shen Z X, Yan H. et al . Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage.  Leukemia. 2001;  15 735-741
    Search in Google Scholar
  • 36 Shen Z X, Chen G Q, Ni J H. 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
    Search in Google Scholar
  • 37 Shen Z X, Shi Z Z, Fang J. et al . All-trans retinoic acid/ As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia.  Proc Natl Acad Sci U S A. 2004;  101 5328-5335
    Search in Google Scholar
  • 38 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. 2005;  82 224-229
    Search in Google Scholar
  • 39 Siu C W, Au W Y, Yung C. et al . Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: implications for long-term cardiac safety.  Blood. 2006;  108 103-106
    Search in Google Scholar
  • 40 Soignet S L, Frankel S R, Douer D. et al . United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia.  J Clin Oncol. 2001;  19 3852-3860
    Search in Google Scholar
  • 41 Soignet S L, Maslak P, Wang Z G. et al . Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide.  N Engl J Med. 1998;  339 1341-1348
    Search in Google Scholar
  • 42 Tallman M S, Nabhan C, Feusner J H, Rowe J M. Acute promyelocytic leukemia: evolving therapeutic strategies.  Blood. 2002;  99 759-767
    Search in Google Scholar
  • 43 Thomas X, Dombret H, Cordonnier C. et al . Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL Study Group. Acute promyelocytic leukemia.  Leukemia. 2000;  14 1006-1013
    Search in Google Scholar
  • 44 Thomas X, Pigneux A, Raffoux E, Huguet F, Caillot D, Fenaux P. Superiority of an arsenic trioxide-based regimen over a historic control combining all-trans retinoic acid plus intensive chemotherapy in the treatment of relapsed acute promyelocytic leukemia.  Haematologica. 2006;  91 996-997
    Search in Google Scholar
  • 45 Trisenox. Summary of Product Characteristics 2002;. Cell Therapeutics Europe 5
    Search in Google Scholar
  • 46 Tsimberidou A M, Estey E, Whitman G J. et al . Extramedullary relapse in a patient with acute promyelocytic leukemia: successful treatment with arsenic trioxide, all-trans retinoic acid and gemtuzumab ozogamicin therapies.  Leuk Res. 2004;  28 991-994
    Search in Google Scholar
  • 47 Unnikrishnan D, Dutcher J P, Varshneya N. et al . Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide.  Blood. 2001;  97 1514-1516
    Search in Google Scholar
  • 48 Wang Z, Zhou J, Lu X, Gong Z, Le X C. Arsenic speciation in urine from acute promyelocytic leukemia patients undergoing arsenic trioxide treatment.  Chem Res Toxicol. 2004;  17 95-103
    Search in Google Scholar
  • 49 Westervelt P, Brown R A, Adkins D R. et al . Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide.  Blood. 2001;  98 266-271
    Search in Google Scholar
  • 50 Zhang P, Wang S, Hu L. et al . Seven years’ summary report on the treatment of acute promyelocytic leukemia with arsenic trioxide - an analysis of 242 cases.  Zhonghua Xue Ye Xue Za Zhi. 2000;  21 67-70
    Search in Google Scholar
  • 51 Zhu J, Koken M H, Quignon F. et al . Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia.  Proc Natl Acad Sci U S A. 1997;  94 3978-3983
    Search in Google Scholar

Priv.-Doz. Dr. Eva Lengfelder

III. Medizinische Universitätsklinik Mannheim

Wiesbadener Straße 7-11

68305 Mannheim

Phone: +49/621/3834110

Fax: +49/621/3834201

Email: eva.lengfelder@med3.ma.uni-heidelberg.de