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

N. Kröger1,+, A. R. Zander1, G. Martinelli2, P. Ferrante3, J. M. Moraleda4, G. A. Da Prada5, T. Demirer6, G. Socie7 and G. Rosti3

1 Department of Bone Marrow Transplantation, University Hospital Hamburg, Hamburg, Germany; 2 Instituto Europeo di Oncologia, Milan, Italy; 3 Department of Oncology and Hematology, Ospedale Civile, Ravenna, Italy; 4 Bone Marrow Transplantation, Hospital General Universitario, Murcia, Spain; 5 Department of Oncology, Fondazione S. Maugeri, Pavia, Italy; 6 Department of Hematology, Oncology University of Ankara, Ankara, Turkey; 7 Bone Marrow Transplantation, Hospital St Louis, Paris, France

Received 8 August 2002; revised 11 October 2002; accepted 20 November 2002


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background:

To determine the incidence of secondary myelodysplasia (sMDS) or acute myeloid leukemia (AML) in node-positive breast cancer patients who received high-dose chemotherapy (HDCT) followed by autologous stem-cell support as adjuvant therapy.

Patients and methods:

The incidence of sMDS/AML was retrospectively assessed in 364 node-positive breast cancer patients who received HDCT followed by autologous stem-cell support as adjuvant therapy between November 1989 and December 1997 and were reported to the European Group for Blood and Marrow Transplantation registry.

Results:

The median age of the patients was 45 years (range 22–62 years). Two hundred and ninety-one patients received peripheral blood stem cells and 55 patients received autologous bone marrow as stem-cell support. The most frequently used conditioning regimen was the STAMP-V regimen (32%), followed by melphalan–thiotepa (22%) and melphalan–mitoxantrone–cyclophosphamide (21%). The 5-year probability of overall survival is 71% (95% CI 65% to 77%). After a median follow-up of 48 months (range 1–108 months) only one case of AML was observed, resulting in a crude incidence of 0.27%. This case of AML was observed 18 months after HDCT consisting of three cycles of epirubicin and cyclophosphamide with a cumulative dose of epirubicin 960 mg and cyclophosphamide 19 g. The French–American–British type of AML was M4, and the cytogenetic analysis showed a translocation t(9;11)(p22;q23). After complete remission following high-dose cytarabine and idarubicin the patient relapsed and died.

Conclusions:

In contrast to patients with malignant lymphoma there seems to be no increased risk of sMDS/AML after HDCT in breast cancer. Continued monitoring is required to confirm this low incidence after a longer follow-up period.

Key words: acute myeloid leukemia, adjuvant therapy, breast cancer, high-dose chemotherapy, secondary myelodysplasia


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Secondary myelodysplasia (sMDS) or acute myeloid leukemia (AML) is a well-known long-term complication in patients who have received chemotherapy or radiation therapy for a previous malignancy [110]. During recent years the number of patients with hematological malignancies or solid tumors who received high-dose chemotherapy (HDCT) followed by autologous stem-cell support has increased substantially. While acute toxicities are well documented and the mortality of the procedure is rather low, clinical interest is focusing on long-term effects including the development of secondary leukemia.

Secondary MDS or AML has become a major problem for long-term survivors with lymphoid malignancies who have received a high-dose chemo/radiotherapy with autologous stem-cell support [36]. Two different types of treatment-related leukemia can be distinguished. The first type results from prior therapy with alkylating agents or radiation therapy and occurs after a latency period of 5–7 years. This type of AML is often preceded by a preleukemic period of sMDS. Up to 90% of the patients with alkylating agent-related sMDS or AML show clonal chromosome aberrations, including monosomy or deletions on chromosomes 5 and/or 7, or complex aberrations involving chromosomes 3, 12, 17 and 21 [7]. The second type of therapy-related leukemia is induced by topoisomerase II targeted drug-like etoposide, anthracyclines or, recently, anthracenediones [810]. This type of AML usually occurs after a median of 2 years and is not preceded by a myelodysplastic syndrome. According to the French–American–British (FAB) classification, more frequently M4 or M5 are observed and cytogenetic analysis shows a high frequency of rearrangements of chromosome band 11q23, t(8;21),t(15;17), inv(16) or t(8;16) as in de novo AML [8, 11]. Despite these more favorable chromosomal aberrations, the secondary leukemias have a poor prognosis. Secondary leukemia after treatment for breast cancer has been reported [1217]. Specific risk factors were: a combination of chemotherapy and radiation therapy; cumulative doses of alkylating agents; and duration of therapy. The International Case Control Study reported a cumulative incidence of 0.7% for breast cancer patients treated with conventional chemotherapy and/or radiation therapy [13].

To date, only limited data have been published studying the risk of secondary leukemia in breast cancer patients who have received HDCT followed by autologous stem-cell transplantation [1921]. Here we report the results of a retrospective study on the incidence of sMDS/AML after HDCT for primary breast cancer patients reported to the European Group for Blood and Marrow Transplantation (EBMT) registry.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patient population and data collection
Patients (494) with node-positive breast cancer had received HDCT followed by autologous stem-cell transplantation as adjuvant therapy between November 1989 and December 1997 in 55 European centers and were reported to the EBMT registry. All centers received a questionnaire for the transplanted patients. Three hundred and sixty-four patients were evaluable to calculate the incidence of sMDS syndromes or leukemias. In 130 patients the answers were incomplete or follow-up was lost. All patients were high-risk patients with three or more involved lymph nodes. The different conditioning regimens are listed in Table 1. Most of the patients received four to six cycles of anthracycline-based induction chemotherapy prior to HDCT. A locoregional radiotherapy was performed in most of the patients, but detailed analysis of radiotherapy was not performed. The median age of the patients at time of stem-cell transplantation was 45 years (range 22–62 years). Stem-cell source was bone marrow in 55 patients and peripheral blood stem cells in 309 patients. The median follow-up was 48 months (range 1–108 months).


View this table:
[in this window]
[in a new window]
 
Table 1. Conditioning regimens for high-dose chemotherapy
 
Statistical analysis
Time to sMDS/AML is the interval from HDCT to diagnosis of sMDS/AML. Patients who did not develop sMDS/AML were censored at date of death or at date of last follow-up for surviving patients. Data were updated as of October 2001. Time to sMDS/AML and the cumulative probability of developing sMDS/AML was estimated by the Kaplan–Meier method.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
After a median follow-up of 48 months (range 1–108 months), one out of 364 patients developed secondary leukemia in this retrospective study. Thus, the crude incidence of secondary leukemia is 0.27%. The one case of AML was observed 18 months after a HDCT protocol consisting of three cycles of epirubicin and cyclophosphamide with a cumulative dose of epirubicin 960 mg and cyclophosphamide 19 g. The FAB type of AML was M4 and the cytogenetic analysis showed a translocation t(9;11)(p22;q23). After complete remission following high-dose cytarabine (ara-C) and idarubicin, the patient relapsed and died 12 months after diagnosis of AML (Tables 2 and 3).


View this table:
[in this window]
[in a new window]
 
Table 2. Patient characteristics
 

View this table:
[in this window]
[in a new window]
 
Table 3. Characteristics of an acute myeloid leukemia (AML) patient
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This retrospective study suggests that HDCT supported by autologous stem-cell transplantation as adjuvant therapy in breast cancer patients results in a low probability of developing sMDS or AML with a crude incidence of 0.27%. The incidence of sMDS/AML does not seem be higher than that reported for conventional adjuvant chemotherapy (Table 4). In a large international case–control study the relative risk of developing sMDS/AML was 10 after conventional alkylating chemotherapy for breast cancer patients [13]. In this study, additional chest-wall irradiation appeared to increase the leukemogenic effect of chemotherapy (relative risk 17.4), and melphalan had a 10 times higher leukemogenic effect than cyclophosphamide. The higher leukemogenic risk of melphalan in the treatment of breast cancer patients was confirmed by the NSABP study, which reported an actuarial risk at 10 years of 1.7%, which was higher than the reported risk of 0.7% from the US cancer registry [12, 18].


View this table:
[in this window]
[in a new window]
 
Table 4. Studies of sMDS/AML in breast cancer patients after conventional and high-dose chemotherapy
 
A much lower incidence for sMDS/AML was reported for cyclophosphamide-based or combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). The Milan group reported an actuarial risk at 10 years of 0.2% for leukemia after CMF treatment and a case–control study from Germany reported an actuarial risk at 10 years of 0.3% after cyclophosphamide-containing chemotherapy [16, 22]. More recently, some studies reported an incidence of sMDS/AML up to 5% in breast cancer patients after adjuvant chemotherapy containing the anthracenedione derivate mitoxantrone, a topoisomerase II targeting drug [10, 14, 17, 23].

In our study, none of the 75 patients who received a mitoxantrone (>=40 mg/m2) based conditioning regimen prior to autologous stem-cell transplantation experienced sMDS or AML during follow-up. The only case of AML in our study occurred after three cycles of high-dose epirubicin and cyclophosphamide. The cumulative dose was epirubicin 960 mg and cyclophosphamide 19 g. Anthracyclines, especially doxorubicin or more recently epidoxorubicin, are now widely used in adjuvant and metastatic treatment of breast cancer. These agents are DNA–topoisomerase II inhibitors and similar to the epipodophyllotoxins usually developed in AML after a median of 2 years without a preceding period of sMDS. The FAB type is mostly M4 or M5 with balanced chromosomal translocation at 11q23 [11]. The estimated risk of developing AML at 10 years after doxorubicin-containing chemotherapy and radiotherapy was 2.5% and 2.7% in two retrospective studies [24, 25]. However, treatment with doxorubicin without radiotherapy had a 10-year risk of sMDS/AML of only 0.5%, which was significantly less than the combination of doxorubicin and radiotherapy (P = 0.01) [25].

High-dose epidoxorubicin in combination with cyclophosphamide was also associated with an increased risk of secondary leukemia in a Canadian study [26]. Recently, Bergh et al. [27] reported in a randomized study comparing HDCT plus autologous stem-cell support with a tailored dose of 5-fluorouracil, cyclophosphamide and epidoxorubicin for high-risk breast cancer patients an increased risk of sMDS/AML in the anthracycline-based group (n = 9), while no sMDS/AML was seen in the high-dose arm. Therefore, it can be argued that the case of AML observed in our study with the typical interval of 18 months, the FAB M4 morphology and the balanced translocation 11q23 might be more related to the anthracycline treatment than to the HDCT as such.

There are few reports of sMDS/AML following HDCT for breast cancer. The Duke University reported in 864 patients who received a high-dose regimen consisting of carmustine, cyclophosphamide and cisplatinum a 4-year probability of developing sMDS/AML of 1.6% [19]. In a Spanish trial involving 229 patients after a median follow-up of 36 months, no case of sMDS/AML was observed [21]. In that trial, in some patients (5%) cytogenetic aberrations were found after HDCT, but these aberrations were only transient and disappeared without developing sMDS or AML. These findings, as well as our data, do not support the hypothesis that HDCT increases the risk of developing sMDS/AML in breast cancer patients. However, these results are in contrast to the reported probability of 14–18% at 5 years after autologous transplantation for lymphoma patients [46]. Risk factors such as age, a higher cumulative dose of alkylating agents or previous radiotherapy, particularly the use of total-body irradiation as conditioning regimen, may have caused the higher incidence in lymphoma patients [36]. However, since it remains unclear whether prior chemotherapy, the type of conditioning regimen or the reinfusion of preleukemic progenitor cells during transplantation causes sMDS/AML, the observed difference in sMDS/AML between lymphoma and breast cancer patients after HDCT is unclear.

We conclude that sMDS/AML is a rare but potential complication following HDCT and autologous stem-cell support in breast cancer patients. The incidence is low compared with the incidence in patients with malignant lymphoma who underwent autologous transplantation. Longer follow-up is necessary to determine late occurrence of sMDS/AML.


    Acknowledgements
 
The following centers participated in this study: Swiss National Bone Marrow Transplant (BMT) Registry, Division of Hematology, Department of Research, Kantonsspital Basel, Basel, Switzerland; Department of Hematology, Huddinge University Hospital, Huddinge, Sweden; Turku University, Central Hospital, Department of Medicine, BMT-Unit, Turku, Finland; Austrian National BMT Registry, BMT Unit, Clinical Immunobiology, University Hospital, Innsbruck, Austria; Oncologia Clinica, Ospedale di Torrete, Ancona-Torrete, Italy; Institut Paoli Calmettes, Marseille, France; Service d’Hématologie, Hôpital Jean Minjoz, Besançon Cedex, France; Service d’Oncologie Médicale, Hôpital Bretonneau, Tours Cedex, France; Centre Jaen Perrin, Clermont-Ferrand, France; Department of Hematology, University Hospital, Lund, Sweden; Oncology-Hematology Department, Ospedale Civile, Ravenna, Italy; Division of Oncology, Hospital Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy; European Institute of Oncology, Milano, Italy; Institute of Haematology, Ospedale Nord, Taranto, Italy; Department of Oncology, San Bortolo Hospital, Vicenza, Italy; Department of Medical Oncology, Ospedale Civile Maggiore, Universita Verona, Italy; Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Sezione di Oncoematologia, Divisione die Medicina I, Ospedale Maggiore, Lodi, Italy; BMT-Unit, K. Dluski Hospital and Institute of Immunology and Experimental Therapy, Wroclaw, Poland; Centre Rene Huguenin, St Cloud, France; Dutch National Registry, Dutch National Registry TYPHON, Department of Hematology, Leiden, The Netherlands; Service des Malades Sanguines et Tumoral, Groupe Hospitalier Paul-Brousse, Villejuif, France; Division of Haematology, Tampere University Hospital, Tampere, Finland; Hospital Universitario La Fe, Servicio de Hematologia, Valencia, Spain; Hopital d’Enfants, Unité de Transplantation Médullaire, Service de Médicine Infantile 2, Vandoeuvre les Nancy, France; Department of Hematology/Oncology, Charles University Hospital, Pilsen, Czech Republic; Hematology Department, Hospital Son Dureta, Palma de Mallorca, Spain; Hospital General Universitario, Unidad de Trasplante de Médula Osea, Servicio de Hematologia, Murcia, Spain; Hopital Tenon, Department of Clinical Oncology, Paris, France; Hellenic Cancer Institute, BMT Unit, St Savas Hospital, Athens, Greece; Division of Oncology, Fondazione S. Maugeri, Pavia, Italy; Department of Internal Medicine I, BMT-Unit, University Hospital, University of Saarland, Homburg, Saar, Germany; Universita di Palermo, Divisione di Ematologia con Trapianto di Midollo Policlinico, Palermo, Italy; Ospedale Civile di Avezzano, Divisione de Medicina Interna, Unita di Oncologia, Luco die Marsi (AQ), Italy; Centre Claudius Regaud, Toulouse, France; C.A.C. Val d’Aurelle, Montpellier, France; Centre Antoine Lacassagne, Service d’Hemato-Oncologie, Nice, France.


    Footnotes
 
+ Correspondence to: Professor N. Kröger, Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. Tel: +49-40-42803-5864; Fax: +49-40-42803-3795; E-mail: nkroeger{at}uke.uni-hamburg.de Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1. Pedersen-Bjergaard J, Philip P. Two different classes of therapy-related and de novo acute myeloid leukemia? Cancer Genet Cytogenet 1991; 55: 119–124.[CrossRef][ISI][Medline]

2. Kantarjian HM, Keating MJ, Walters RS et al. Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic and prognostic features. J Clin Oncol 1986; 4: 1748–1757.[Abstract]

3. Marolleau JP, Brice P, Morel P, Gisselbrecht C. Secondary acute leukemia after autologous bone marrow transplantation for malignant lymphomas. J Clin Oncol 1993; 11: 590–598.[ISI][Medline]

4. Darrington DL, Vose JM, Anderson JR et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 1994; 12: 2527–2534.[Abstract]

5. Stone RM, Neuberg D, Soiffer R et al. Myelodysplasic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 1994; 12: 2535–2542.[Abstract]

6. Milligan DW, Ruiz De Elvira MC, Kolb HJ et al. Secondary leukemia and myelodysplasia after autografting for lymphoma: results from the EBMT. Br J Haematol 1999; 106: 1020–1026.[CrossRef][ISI][Medline]

7. LeBeau MM, Albain KS, Larson RA et al. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no 5 and 7. J Clin Oncol 1986; 4: 325–345.[Abstract]

8. Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs. Biochem Biophys Acta 1998; 1400: 233–255.[ISI][Medline]

9. Kollmannsberger C, Hartmann JT, 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.[CrossRef][ISI][Medline]

10. Linassier C, Barin C, Calais G 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.[Abstract]

11. Pedersen-Bjergaard J, Andersen MK, Johansson B. Balanced chromosome aberrations in leukemias following chemotherapy with DNA–topoisomerase II inhibitors. J Clin Oncol 1998; 16: 1897–1898.[ISI][Medline]

12. Curtis RE, Boice JD, Moloney WC et al. Leukemia following chemotherapy for breast cancer. Cancer Res 1990; 50: 2741–2746.[Abstract]

13. Curtis RE, Boice JD Jr, Stovall M et al. Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 1992; 326: 1745–1751.[Abstract]

14. Cremin P, Flattery M, McCann SR, Daly PA. 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.[Abstract]

15. Tallman MS, Gray R, Bennett JM 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.[Abstract]

16. Haas JF, Kittelmann B, Mehner WH et al. Risk of leukemia in ovarian tumor and breast cancer patients following treatment by cyclophosphamide. Br J Cancer 1987; 55: 213–218.[ISI][Medline]

17. Saso R, Kulkarni S, Mitchell P et al. Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma. Br J Cancer 2000; 83: 91–94.[CrossRef][ISI][Medline]

18. Fisher B, Rockette H, Fisher ER et al. Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience. J Clin Oncol 1985; 12: 1640–1658.

19. Laughlin MJ, McGaughey DS, Crews JR et al. Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant. J Clin Oncol 1998; 16: 1008–1012.[Abstract]

20. Roman-Unfer S, Bitran JD, Hanaver S et al. Acute myeloid leukemia and myelodysplasia following intensive chemotherapy for breast cancer. Bone Marrow Transplant 1995; 16: 163–168.[ISI][Medline]

21. Martinez-Climent JA, Comes AM, Vizcarra E et al. Chromosomal abnormalities in women with breast cancer after autologous stem cell transplantation are infrequent and may not predict development of therapy-related leukemia or myelodysplastic syndrome. Bone Marrow Transplant 2000; 25: 1203–1208.[CrossRef][ISI][Medline]

22. Valagussa P, Moliterni A, Terenziani M et al. Second malignancies following CMF-based adjuvant chemotherapy in resectable breast cancer. Ann Oncol 1994; 5: 803–808.[Abstract]

23. Chaplain G, Milan C, Sgro C et al. Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: a population-based study. J Clin Oncol 2000; 18: 2836–2842.[Abstract/Free Full Text]

24. Buzdar R, Iwaniec J, Kau S et al. Secondary leukemia following adjuvant doxorubicin-containing chemotherapy for stage II or III breast cancer. Proc Am Soc Clin Oncol 1991; 10: 59a (Abstr 112).

25. Diamandidou E, Buzdar AU, Smith TL et al. 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.[Abstract]

26. Shepherd L, Ottaway J, Myles J et al. Therapy-related leukemia associated with high-dose 4-epi-doxorubicin and cyclophosphamide used as adjuvant chemotherapy for breast cancer. J Clin Oncol 1994; 12: 2514–2515.[ISI][Medline]

27. Bergh J, Wiklund T, Erikstein B et al. Tailored fluorouracil, epirubicin and cyclophosphamide compared with marrow supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomized trial. Lancet 2000; 356: 1384–1391.[CrossRef][ISI][Medline]





This Article
Abstract
Full Text (PDF)
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (4)
Disclaimer
Request Permissions
Google Scholar
Articles by Kröger, N.
Articles by Rosti, G.
PubMed
PubMed Citation
Articles by Kröger, N.
Articles by Rosti, G.