Zentralbl Gynakol 2005; 127(4): 235-241
DOI: 10.1055/s-2005-836562
Übersicht

© Georg Thieme Verlag Stuttgart · New York

Therapie-induzierte Leukämien - ein zu wenig beachtetes Problem der medikamentösen Tumortherapie?

Therapy-induced Leukemia - An Underestimated Complication of Antineoplastic Chemotherapy?U. Dührsen1
  • 1Klinik für Hämatologie, Universitätsklinikum Essen
Further Information

Publication History

Publication Date:
22 July 2005 (online)

Zusammenfassung

Alkylanzien und Topoisomerase-II-Hemmstoffe können Therapie-induzierte akute myeloische Leukämien und Myelodysplasien auslösen. Die Häufigkeit des Auftretens hängt von der Art der verwendeten Substanz, ihrer Dosierung und der Behandlungsdauer ab. Mit den in der adjuvanten Therapie des Mammakarzinoms üblicherweise verwendeten Therapieprotokollen, wie dem CMF- oder AC-Schema, liegt die Leukämierate nach 10 Jahren bei 0,2 bis 0,5 %. Eine Intensivierung der Chemotherapie oder zusätzliche strahlentherapeutische Maßnahmen führen zu einer deutlichen Zunahme der Leukämieinzidenz. Die schlechte Prognose Therapie-induzierter Leukämien und Myelodysplasien begründet die Forderung nach einer möglichst präzisen Identifikation von Patienten, die von adjuvanten Therapiemaßnahmen tatsächlich profitieren.

Abstract

Alkylating agents and topoisomerase II inhibitors are mutagenic cytotoxic drugs which may induce therapy-related acute myeloid leukemia or myelodysplasia. The frequency of these complications depends on the type of agent used, its dosage, and the duration of treatment. Commonly used protocols for adjuvant chemotherapy of breast cancer, such as the CMF or AC protocols, are associated with a leukemia rate of 0.2 to 0.5 % after 10 years. Intensification of chemotherapy or additional radiotherapy lead to a significant increase in the incidence of leukemia. The prognosis of therapy-related leukemia is dismal. Therefore, it appears mandatory to restrict adjuvant chemotherapy to those patients who are the most likely to benefit from it.

Literatur

  • 1 Shapiro C L, Recht A. Side effects of adjuvant treatment of breast cancer.  N Engl J Med. 2001;  344 1997-2008
  • 2 Levine E G, Bloomfield C D. Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure.  Semin Oncol. 1992;  19 47-84
  • 3 Karp J E, Smith M A. The molecular pathogenesis of treatment-induced (secondary) leukemias: foundations for treatment and prevention.  Semin Oncol. 1997;  24 103-113
  • 4 Kollmannsberger C, Hartmann J T, Kanz L, Bokemeyer C. Risk of secondary myeloid leukemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies.  J Cancer Res Clin Oncol. 1998;  124 207-214
  • 5 Weldon C B, Jaffe B M, Kahn M J. Therapy-induced leukemias and myelodysplastic syndromes after breast cancer treatment: an underemphasized clinical problem.  Ann Surg Oncol. 2002;  9 738-744
  • 6 World Health Organization .Classification of Tumours - Pathology and Genetics - Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon 2001
  • 7 Curtis R E, Boice J D, Moloney W C, Ries L G, Flannery J T. Leukemia following chemotherapy for breast cancer.  Cancer Res. 1990;  50 2741-2746
  • 8 Bennett J M, Catovsky D, Daniel M T, Flandrin G, Galton D A, Gralnick H R. et al . Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group.  Ann Intern Med. 1985;  103 620-625
  • 9 Bennett J M, Catovsky D, Daniel M T, Flandrin G, Galton D A, Gralnick H R. et al . Proposals for the classification of the myelodysplastic syndromes.  Br J Haematol. 1982;  51 189-199
  • 10 Greenberg P, Cox C, LeBeau M M, Fenaux P, Morel P, Sanz G. et al . International scoring system for evaluating prognosis in myelodysplastic syndromes.  Blood. 1997;  89 2079-2088
  • 11 Pagano L, Pulsoni A, Tosti M E, Avvisati G, Mele L, Mele M. et al . Clinical and biological features of acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute leukaemia.  Br J Haematol. 2001;  112 109-117
  • 12 Pedersen-Bjergaard J, Philip P, Larsen S O, Andersson M, Daugaard G, Ersboll J. et al . Therapy-related myelodysplasia and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series.  Leukemia. 1993;  7 1975-1986
  • 13 Mauritzson N, Albin M, Rylander L, Billström R, Ahlgren T, Mikoczy Z. et al . Pooled analysis of clinical and cytogenetic features in treatment-related and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analyzed 1976-1993 and on 5 098 unselected cases reported in the literature 1974-2001.  Leukemia. 2002;  16 2366-2378
  • 14 Pedersen-Bjergaard J, Sigsgaard T C, Nielsen D, Gjedde S B, Philip P, Hansen M. et al . Acute monocytic or myelomonocytic leukemia with balanced chromosome translocations to band 11q23 after therapy with 4-epi-doxorubicin and cisplatin or cyclophosphamide for breast cancer.  J Clin Oncol. 1992;  10 1444-1451
  • 15 Hoffmann L, Möller P, Pedersen-Bjergaard J, Waage A, Pedersen M, Hirsch F R. Therapy-related acute promyelocytic leukemia with t(15;17) (q22;q12) following chemotherapy with drugs targeting DNA topoisomerase II. A report of two cases and a review of the literature.  Ann Oncol. 1995;  6 781-788
  • 16 Carli P M, Sgro C, Parchin-Geneste N, Isambert N, Mugneret F, Girodon F. et al . Increase therapy-related leukemia secondary to breast cancer.  Leukemia. 2000;  14 1014-1017
  • 17 Crump M, Tu D, Shepherd L, Levine M, Bramwell V, Pritchard K. Risk of acute leukemia following epirubicin-based adjuvant chemotherapy: a report from the National Cancer Institute of Canada Clinical Trials Group.  J Clin Oncol. 2003;  21 3066-3071
  • 18 Smith R E, Bryant J, DeCillis A, Anderson S. Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience.  J Clin Oncol. 2003;  21 1195-1204
  • 19 Curtis R E, Hankey B F, Myers M H, Young J L. Risk of leukemia associated with the first course of cancer treatment: an analysis of the Surveillance, Epidemiology, and End Results Program experience.  J Natl Cancer Inst. 1984;  72 531-544
  • 20 Fisher B, Rockette H, Fisher E R, Wickerham D L, Redmond C, Brown A. Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience.  J Clin Oncol. 1985;  3 1640-1658
  • 21 Haas J F, Kittelmann B, Mehnert W H, Staneczek W, Möhner M, Kaldor J M. et al . Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide.  Br J Cancer. 1987;  55 213-218
  • 22 Curtis R E, Boice J D, Stovall M, Bernstein L, Greenberg R S, Flannery J T. et al . Risk of leukemia after chemotherapy and radiation treatment for breast cancer.  N Engl J Med. 1992;  326 1745-1751
  • 23 Diamandidou E, Buzdar A U, Smith T L, Frye D, Witjaksono M, Hortobagyi G N. Treatment-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience.  J Clin Oncol. 1996;  14 2722-2730
  • 24 Bernard-Marty C, Mano M, Paesmans M, Accettura C, Munoz-Bermeo R, Richard T. et al . Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients.  Ann Oncol. 2003;  14 693-698
  • 25 Valagussa P, Moliterni A, Terenziani M, Zambetti M, Bonadonna G. Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer.  Ann Oncol. 1994;  5 803-808
  • 26 Tallman M S, Gray R, Bennett J M, Variakojis D, Robert N, Wood W C. et al . Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience.  J Clin Oncol. 1995;  13 1557-1563
  • 27 Yagita M, Ieki Y, Onishi R, Huang C L, Adachi M, Horiike S. et al . Therapy-related leukemia and myelodysplasia following oral administration of etoposide for recurrent breast cancer.  Int J Oncol. 1998;  13 91-96
  • 28 Saso R, Kulkarni S, Mitchell P, Treleaven J, Swansbury G J, Mehta J. et al . Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma.  Br J Cancer. 2000;  83 91-94
  • 29 Chaplain G, Milan C, Sgro C, Carli P M, Bonithon-Kopp C. Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: a population-based study.  J Clin Oncol. 2000;  18 2836-2842
  • 30 Cremin P, Flattery M, McCann S R, Daly P A. Myelodysplasia and acute myeloid leukaemia following adjuvant chemotherapy for breast cancer using mitoxantrone and methotrexate with or without mitomycin.  Ann Oncol. 1996;  7 745-746
  • 31 Linassier C, Barin C, Calais G, Letortorec S, Bremond J L, Delain M. et al . Early secondary acute myelogenous leukemia in breast cancer patients after treatment with mitoxantrone, cyclophosphamide, fluorouracil and radiation therapy.  Ann Oncol. 2000;  11 1289-1294
  • 32 Arriagada R, Gutierrez J. Anthracyclines: is more, better and/or more dangerous?.  Ann Oncol. 2003;  14 663-665
  • 33 Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmström P. et al . Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study.  Lancet. 2000;  356 1384-1391
  • 34 Roman-Unfer S, Bitran J D, Hanauer S, Johnson L, Rita D, Booth C. et al . Acute myeloid leukemia and myelodysplasia following intensive chemotherapy for breast cancer.  Bone Marrow Transplant. 1995;  16 163-168
  • 35 Laughlin M J, McGaughey D S, Crews J R, Chao N J, Rizzieri D, Ross M. et al . Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant.  J Clin Oncol. 1998;  16 1008-1012
  • 36 Kröger N, Zander A R, Martinelli G, Ferrante P, Moraleda J M, Da Prada G A. et al . Low incidence of secondary myelodysplasia and acute myeloid leukemia after high-dose chemotherapy as adjuvant therapy for breast cancer patients: a study by the Solid Tumors Working Party of the European Group for Blood and Marrow Transplantation.  Ann Oncol. 2003;  14 554-558
  • 37 Stone R M, Neuberg D, Soiffer R, Takvorian T, Whelan M, Rabinowe S N. et al . Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma.  J Clin Oncol. 1994;  12 2535-2542
  • 38 Miller J S, Arthur D C, Litz C E, Neglia J P, Miller W J, Weisdorf D J. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy.  Blood. 1994;  83 3780-3786
  • 39 Friedberg J W, Neuberg D, Stone R M, Alyea E, Jallow H, LaCasce A. et al . Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma.  J Clin Oncol. 1999;  17 3128-3135
  • 40 Sobecks R M, Le Beau M M, Anastasi J, Williams S F. Myelodysplasia and acute leukemia following high-dose chemotherapy and autologous bone marrow or peripheral blood stem cell transplantation.  Bone Marrow Transplant. 1999;  23 1161-1165
  • 41 Govindarajan R, Jagannath S, Flick J T, Vesole D H, Sawyer J, Barlogie B. et al . Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma.  Br J Haematol. 1996;  95 349-353
  • 42 Seymour J F, Juneja S K, Campbell L J, Ellims P H, Estey E H, Prince H M. Secondary acute myeloid leukemia with inv(16): report of two cases following paclitaxel-containing chemotherapy and review of the role of intensified ara-C therapy.  Leukemia. 1999;  13 1735-1740
  • 43 Preston D L, Kusumi S, Tomonaga M, Izumi S, Ron E, Kuramoto A. et al . Cancer incidence in atomic bomb survivors. Part III. Leukemia, lymphoma and multiple myeloma, 1950-1987.  Radiat Res. 1994;  137 (2 Suppl) S68-S97
  • 44 Curtis R E, Boice J D, Stovall M, Flannery J T, Moloney W C. Leukemia risk following radiotherapy for breast cancer.  J Clin Oncol. 1989;  7 21-29
  • 45 Lavey R S, Eby N L, Prosnitz L R. Impact of radiation therapy and/or chemotherapy on the risk for a second malignancy after breast cancer.  Cancer. 1990;  66 874-881
  • 46 Andersson M, Storm H H, Mouridsen H T. Incidence of new primary cancers after adjuvant tamoxifen therapy and radiotherapy for early breast cancer.  J Natl Cancer Inst. 1991;  83 1013-1017
  • 47 Rutqvist L E, Johansson H, Signomklao T, Johansson U, Fornander T, Wilking N. Stockholm Breast Cancer Study Group . Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies.  J Natl Cancer Inst. 1995;  87 645-651
  • 48 Kaldor J M, Day N E, Pettersson F, Clarke E A, Pedersen D, Mehnert W. et al . Leukemia following chemotherapy for ovarian cancer.  N Engl J Med. 1990;  322 1-6
  • 49 Pedersen-Bjergaard J, Ersboll J, Sorensen H M, Keiding N, Larsen S O, Philip P. et al . Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Comparison with results obtained in patients treated for Hodgkin's disease and ovarian carcinoma with other alkylating agents.  Ann Intern Med. 1985;  103 195-200
  • 50 Rose P G, Rodriguez M, Waggoner S, Greer B E, Horowitz I R, Fowler J M. et al . Phase I study of paclitaxel, carboplatin, and increasing days of prolonged oral etoposide in ovarian, peritoneal, and tubal carcinoma: a gynecologic oncology group study.  J Clin Oncol. 2000;  18 2957-2962
  • 51 Henderson I C. Breast cancer therapy - the price of success.  N Engl J Med. 1992;  326 1774-1775
  • 52 van de Vijver M J, He Y D, van't Veer L J, Dai H, Hart A A, Voskuil D W. et al . A gene-expression signature as a predictor of survival in breast cancer.  N Engl J Med. 2002;  347 1999-2009
  • 53 Wang Y, Klijn J G, Zhang Y, Sieuwerts A M, Look M P, Yang F. et al . Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.  Lancet. 2005;  365 671-679
  • 54 Felix C A, Walker A H, Lange B J, Williams T M, Winick N J, Cheung N K. et al . Association of CYP3A4 genotype with treatment-related leukemia.  Proc Natl Acad Sci U S A. 1998;  95 13 176-13 181
  • 55 Allan J M, Wild C P, Rollinson S, Willett E V, Moorman A V, Dovey G J. et al . Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia.  Proc Natl Acad Sci U S A. 2001;  98 11 592-11 597
  • 56 Haase D, Binder C, Bünger J, Fonatsch C, Streubel B, Schnittger S. et al . Increased risk for therapy-associated hematologic malignancies in patients with carcinoma of the breast and combined homozygous gene deletions of glutathione transferases M1 and T1.  Leuk Res. 2002;  26 249-254

Prof. Dr. U. Dührsen

Direktor der Klinik für Hämatologie · Zentrum für Innere Medizin · Universitätsklinikum Essen · Universität Duisburg-Essen

Hufelandstraße 55

45122 Essen

Phone: 02 01/7 23 24 17

Fax: 02 01/7 23 59 28

Email: ulrich.duehrsen@uni-essen.de