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Dtsch Med Wochenschr 2001; 126(39): 1073-1079
DOI: 10.1055/s-2001-17496
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© Georg Thieme Verlag Stuttgart · New York

Aktuelle Therapiekonzepte bei akuter Promyelozytenleukämie

Current therapeutic concept of acute promyelocytic leukaemiaE. Lengfelder1 , R. Hehlmann1 , Th Büchner2
  • 1III. Medizinische Universitätsklinik Mannheim (Direktor: Prof. Dr. R. Hehlmann), Universität Heidelberg
  • 2Medizinische Universitätsklinik A (Direktor Prof. Dr. W. Berdel), Universität Münster
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Publication Date:
27 September 2001 (online)

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Die herkömmliche Strategie zur Behandlung akuter Leukämien beruht auf dem Prinzip, den leukämischen Klon mit Hilfe einer intensiven Chemotherapie möglichst vollständig zu eradizieren und dadurch eine Heilung zu erzielen. Hauptansatzpunkt der Zytostatika ist die Blockierung zentraler Mechanismen der Zellreplikation. Die Grenzen dieser Therapie liegen in der unspezifischen, oft unzureichenden Wirkung und der hohen Toxizität. Ein neuerer Ansatz, der diese Probleme zu umgehen versucht, beruht auf einer selektiv auf die Leukämiezelle gerichteten, gezielt am Pathomechanismus des Leukämietyps angreifenden Therapie.

Bei der akuten Promyelozytenleukämie (APL), einem Subtyp der akuten myeloischen Leukämie (AML-M3), hat ein solches Therapieprinzip in Form einer APL-spezifischen differenzierenden Therapie mit dem Vitamin-A-Säurederivat All-trans-Retinsäure (ATRA) bereits seit Ende der 80er Jahre Eingang in die klinische Praxis gefunden. Die APL war die erste Leukämieform bei der eine spezifisch wirksame Substanz verfügbar war. Außerdem sind die therapeutisch relevanten molekularen Aberrationen bekannt. Die APL kann deshalb als Modellkrankheit für Fortschritte durch die Anwendung einer Pathogenese-orientierten Therapie bei akuter Leukämie angesehen werden.

Literatur

  • 1 Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon M F. Acute promyelocytic leukemia. Results of treatment by Daunorubicin.  Blood. 1973;  41 489-496
    Search in Google Scholar
  • 2 Büchner T, Hiddemann W, Wörmann B. et al . Double induction strategy for acute myeloid leukemia. The effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine. A randomized trial by the German AML Cooperative Group.  Blood. 1999;  93 6116-4124
    Search in Google Scholar
  • 3 Burnett A K, Grimwade D, Solomon E, Wheatley K, Goldstone A H. Presenting white blood cell counts and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid. Results of the randomized MRC trial.  Blood. 1999;  93 4131-4143
    Search in Google Scholar
  • 4 Chen Z Y, Xue Y Q, Zhang R. et al . A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients.  Blood. 1991;  78 1413-1419
    Search in Google Scholar
  • 5 Chen G Q, Shi X G, Tang W. et al . Use of Trioxide (As203)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 Chen Z. Treatment of acute promyelocytic leukemia with arsenic compounds. In vitro and in vivo studies.  Semin Hematol. 2001;  38 26-36
    Search in Google Scholar
  • 7 De Botton S, Dombret H, Sanz M. et al . Incidence, clinical features and outcome of all trans-retinoid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia.  Blood. 1998;  92 2712-2718
    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 De Witte T, Suciu S, Zittoun R. et al . The type of anthrazykline administered during remission induction and consolidation therapy of AML has an impact on feasibility of subsequent autologous or allogeneic transplantation and induced marrow toxicity: preliminary results of the EORTC-GIMEMA AML-10 randomized trial.  Blood. 2000;  96 503a (suppl 1))
    Search in Google Scholar
  • 10 Diviero D, Rossi V, Avvisati G. et al . Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARα fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter »AIDA« trial.  Blood. 1998;  92 784-789
    Search in Google Scholar
  • 11 Estey E H, Giles F, Kantarjian H. et al . Molecular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia.  Blood. 1999;  94 2230-2235
    Search in Google Scholar
  • 12 Fenaux P, Castaigne S, Dombret H. et al . All-trans retinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia. A pilot study on 26 cases.  Blood. 1992;  80 2176-2181
    Search in Google Scholar
  • 13 Fenaux P, Le D eley MC, Castaigne S. et al . Effect of all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicentar randomized study.  Blood. 1993;  82 3241-3249
    Search in Google Scholar
  • 14 Fenaux P, Chastang C, Chevret S. et al . A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia.  Blood. 1999;  94 1192-1200
    Search in Google Scholar
  • 15 Frankel S R, Eardley A, Heller G. et al . All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study.  Ann Intern Med. 1994;  120 278-286
    Search in Google Scholar
  • 16 Grimwade D. The pathogenesis of acute promyelocytic leukemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease.  Br J Haematol. 1999;  106 591-613
    Search in Google Scholar
  • 17 Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARα underlie molecular pathogenesis and treatment in acute promyelocytic leukemia.  Blood. 1998;  91 2634-2642
    Search in Google Scholar
  • 18 Head D, Kenneth J K, Weick J. et al . Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia.  Blood. 1995;  86 1717-1728
    Search in Google Scholar
  • 19 Hiddemann W. Cytosine arabinoside in the treatment of acute myeloid leukemia. The role and place of high-dose regimens.  Ann Hematol. 1991;  62 119-128
    Search in Google Scholar
  • 20 Huang M, Ye Y, Chen S, Chai S, Lu J X, Lin Z, Gu L, Wang Z. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia.  Blood. 1988;  72 567-572
    Search in Google Scholar
  • 21 Kakizuka A, Miller W H, Umesono K. et al . Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML.  Cell. 1991;  66 663-674
    Search in Google Scholar
  • 22 Kanamaru A, Takemoto Y, Tanimoto M. et al . All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia.  Blood. 1995;  85 1202-1206
    Search in Google Scholar
  • 23 Kantarjian H M, Keating M J, Walters R S, Smith T L, McCredie K, Freireich E J. Role of maintenance chemotherapy in acute promyelocytic leukemia.  Cancer. 1987;  59 1258-1263
    Search in Google Scholar
  • 24 Lengfelder E, Reichert A, Hehlmann R. et al . Effects of high dose cytarabin as part of double induction strategy in acute promyelocytic leukemia and results of combination with all-trans retinoic acid.  Blood. 1997;  90 330a (suppl 1))
    Search in Google Scholar
  • 25 Lengfelder E, Reichert A, Schoch C. et al . Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid. Effects in patients with newly diagnosed acute promyelocytic leukemia.  Leukemia. 2000;  14 1362-1370
    Search in Google Scholar
  • 26 Lo Coco F, Diverio D, Avvisati G. et al . Therapy of molecular relapse in acute promyelocytic leukemia.  Blood. 1999;  94 2225-2229
    Search in Google Scholar
  • 27 Mandelli F, Labopoin M, Granena A. et al . European survey of bone marrow transplantation in acute promyelocytic leukemia (M3).  Bone Marrow Transplantation. 1994;  14 293-298
    Search in Google Scholar
  • 28 Mandelli F, Diviero D, Avvisati G. et al . Molecular remission in PML/RAR(-positive acute promyelocytic leukemia by combined all-trans retinoic acid and Idarubicin (AIDA) therapy.  Blood. 1997;  90 1014-1021
    Search in Google Scholar
  • 29 Niu C, Yan H, Yu T, Sun H P. 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 Runde V, Aul C. Treatment of acute promyelocytic leukemia.  Onkologie. 1992;  15 356-363
    Search in Google Scholar
  • 31 Sanz M A, Martín G, Rayón C. et al . A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARa-positve acute promyelocytic leukemia.  Blood. 1999;  94 3015-3021
    Search in Google Scholar
  • 32 Sanz M A, Lo C oco F, Martín G. et al . Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia. A joint study of the PETHEMA and GIMEMA cooperative groups.  Blod. 2000;  96 1247-1253
    Search in Google Scholar
  • 33 Saußele S, Lengfelder E, Weißer A. et al . Monitoring of minimal residual disease by RT-PCR of PML/RARα und RARα/PML fusion transcripts in acute promyelocytic leukemia.  Onkologie. 2000;  23 95 (Suppl 7))
    Search in Google Scholar
  • 34 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
  • 35 Tallman M S, Kwaan H C. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia.  Blood. 1992;  79 543-553
    Search in Google Scholar
  • 36 Tallman M S, Andersen J W, Schiffer C A. et al . All-trans retinoic acid in acute promyelocytic leukemia.  N Engl J Med. 1997;  337 1021-1028
    Search in Google Scholar
  • 37 Tallman M S, Andersen J W, Schiffer C A. et al . All-trans retinoic acid in acute promyelocytic leukemia long-term outcome results and prognostic factor analysis from intergroup protocol 0129.  Blood. 1999;  94 698a (Suppl 1))
    Search in Google Scholar
  • 38 Tallman M S, Andersen J W, Schiffer C A. et al . Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome.  Blood. 2000;  95 90-95
    Search in Google Scholar
  • 39 Warrell R P. Retinoic resistance in acute promyelocytic leukemia. New mechanisms, strategies, and implications.  Blood. 1993;  82 1949-1953
    Search in Google Scholar
  • 40 Warrell R P, Maslak P, Eardley A, Heller G, Miller W H, Frankel S R. Treatment of acute promyelocytic leukemia with all-trans retinoic acid. An update of the New York experience.  Leukemia. 1994;  8 929-933
    Search in Google Scholar
  • 41 Wiley J S, Firkin F C. Reduction of pulmonary toxicity by predisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia.  Leukemia. 1995;  9 774-778
    Search in Google Scholar

Korrespondenz

PD Dr. Eva Lengfelder

III. Med. Klinik Mannheim

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68305 Mannheim

Phone: 0621/383-4110

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