Journal Article
. 2003 Mar; 21(7):1195-204.
doi: 10.1200/JCO.2003.03.114.

Acute myeloid leukemia and myelodysplastic syndrome after doxorubicin-cyclophosphamide adjuvant therapy for operable breast cancer: the National Surgical Adjuvant Breast and Bowel Project Experience

Roy E Smith 1 John Bryant  Arthur DeCillis  Stewart Anderson  National Surgical Adjuvant Breast and Bowel Project Experience  
Affiliations
  • PMID: 12663705
  •     80 citations

Abstract

Purpose: We reviewed data from all adjuvant NSABP breast cancer trials that tested regimens containing both doxorubicin (A) and cyclophosphamide (C) to characterize the incidence of subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Materials And Methods: Six complete NSABP trials have investigated AC regimens (B-15, B-16, B-18, B-22, B-23, and B-25). Six distinct AC regimens have been tested and are distinguished by differences in cyclophosphamide intensity and cumulative dose and by the presence or absence of mandated prophylactic support with growth factor and ciprofloxacin. In all regimens, A was given at 60 mg/m(2) q 21 days x 4. C was given as follows: 600 mg/m(2) q 21 days x 4 ("standard AC"); 1,200 mg(2) q 21 days x 2; 1,200 mg/m(2) q 21 days x 4; 2,400 mg/m(2) q 21 days x 2; and 2,400 mg/m(2) q 21 days x 4. Occurrence of AML/MDS was summarized by incidence per 1,000 patient-years at risk and by cumulative incidence. Rates were compared across regimens, by age, and by treatment with or without breast radiotherapy.

Results: The incidence of AML/MDS was sharply elevated in the more intense regimens. In patients receiving two or four cycles of C at 2,400 mg/m(2) with granulocyte colony-stimulating factor (G-CSF) support, cumulative incidence of AML/MDS at 5 years was 1.01% (95% confidence interval [CI], 0.63% to 1.62%), compared with 0.21% (95% CI, 0.11% to 0.41%) for patients treated with standard AC. Patients who received breast radiotherapy experienced more secondary AML/MDS than those who did not (RR = 2.38, P=.006), and the data indicated that G-CSF does may possibly also be independently correlated with increased risk.

Conclusion: AC regimens employing intensified doses of cyclophosphamide requiring G-CSF support were characterized by increased rates of subsequent AML/MDS, although the incidence of AML/MDS was small relative to that of breast cancer relapse. Breast radiotherapy appeared to be associated with an increased risk of AML/MDS.

Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy.
Pauline T Truong, Ivo A Olivotto, +2 authors, Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer.
CMAJ, 2004 Apr 14; 170(8). PMID: 15078851    Free PMC article.
Radiation-induced malignancies following radiotherapy for breast cancer.
R Roychoudhuri, H Evans, D Robinson, H Møller.
Br J Cancer, 2004 Aug 05; 91(5). PMID: 15292931    Free PMC article.
Cancer survivorship: the concept and the increasingly recognized reality.
Maurie Markman.
Curr Oncol Rep, 2006 Mar 02; 8(2). PMID: 16507215
Radiation therapy after breast-conserving surgery.
Naoyuki Shigematsu, Atsuya Takeda, +6 authors, Atsushi Kubo.
Radiat Med, 2006 Sep 09; 24(5). PMID: 16958420
Review.
Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group.
Smita Bhatia, Mark D Krailo, +11 authors, James S Miser.
Blood, 2006 Sep 21; 109(1). PMID: 16985182    Free PMC article.
Family history of breast cancer and young age at diagnosis of breast cancer increase risk of second primary malignancies in women: a population-based cohort study.
M Prochazka, P Hall, F Granath, K Czene.
Br J Cancer, 2006 Oct 07; 95(9). PMID: 17024122    Free PMC article.
Oxidative DNA base damage in MCF-10A breast epithelial cells at clinically achievable concentrations of doxorubicin.
Ewa Gajewski, Shikha Gaur, +3 authors, James H Doroshow.
Biochem Pharmacol, 2007 Apr 21; 73(12). PMID: 17445777    Free PMC article.
Does chemotherapy-induced neutropaenia result in a postponement of adjuvant or neoadjuvant regimens in breast cancer patients? Results of a retrospective analysis.
M Debled, N Houédé, +4 authors, Louis Mauriac.
Br J Cancer, 2007 Nov 15; 97(12). PMID: 18000502    Free PMC article.
A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells.
Ingrid Ibarra, Yaniv Erlich, +2 authors, Gregory J Hannon.
Genes Dev, 2007 Dec 15; 21(24). PMID: 18079172    Free PMC article.
Breast cancer and chronic myeloid leukemia: a short review.
Hüseyin Engin, Ayla Gökmen Aköz.
Int J Hematol, 2008 Jan 15; 86(5). PMID: 18192121
Review.
Canadian supportive care recommendations for the management of neutropenia in patients with cancer.
C T Kouroukis, S Chia, +4 authors, J Mikhael.
Curr Oncol, 2008 Mar 05; 15(1). PMID: 18317581    Free PMC article.
Second cancers in patients with the Ewing sarcoma family of tumours.
Fariba Navid, Catherine Billups, +2 authors, Carlos Rodriguez-Galindo.
Eur J Cancer, 2008 Mar 21; 44(7). PMID: 18353632    Free PMC article.
Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis.
Athanasia D Panopoulos, Stephanie S Watowich.
Cytokine, 2008 Apr 11; 42(3). PMID: 18400509    Free PMC article.
Highly Cited. Review.
Recurrent metastatic neuroblastoma followed by myelodysplastic syndrome: possible leukemogenic role of temozolomide.
Brian H Kushner, Michael P Laquaglia, +2 authors, Nai-Kong V Cheung.
Pediatr Blood Cancer, 2008 Jun 24; 51(4). PMID: 18570300    Free PMC article.
Therapy-related myeloid leukemia.
Lucy A Godley, Richard A Larson.
Semin Oncol, 2008 Aug 12; 35(4). PMID: 18692692    Free PMC article.
Review.
Choice and interpretation of statistical tests used when competing risks are present.
James J Dignam, Maria N Kocherginsky.
J Clin Oncol, 2008 Aug 20; 26(24). PMID: 18711194    Free PMC article.
Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues.
Nobuko Hijiya, Kirsten K Ness, Raul C Ribeiro, Melissa M Hudson.
Cancer, 2008 Dec 17; 115(1). PMID: 19072983    Free PMC article.
Review.
Reduced risk of secondary leukemia with fewer cycles of dose-intensive induction chemotherapy in patients with neuroblastoma.
Brian H Kushner, Kim Kramer, +4 authors, Nai-Kong V Cheung.
Pediatr Blood Cancer, 2009 Jan 17; 53(1). PMID: 19148951    Free PMC article.
Ten-year follow-up of unrelated volunteer granulocyte donors who have received multiple cycles of granulocyte-colony-stimulating factor and dexamethasone.
Karen Quillen, Phyllis Byrne, Yu Ying Yau, Susan F Leitman.
Transfusion, 2009 Feb 27; 49(3). PMID: 19243544    Free PMC article.
Recent advances in systemic therapy: advances in adjuvant systemic chemotherapy of early breast cancer.
Sara López-Tarruella, Miguel Martín.
Breast Cancer Res, 2009 Apr 07; 11(2). PMID: 19344489    Free PMC article.
Review.
Oncologist use of the Adjuvant! model for risk communication: a pilot study examining patient knowledge of 10-year prognosis.
Jeffrey K Belkora, Hope S Rugo, +3 authors, Laura J Esserman.
BMC Cancer, 2009 Apr 30; 9. PMID: 19400938    Free PMC article.
Screening for clonal hematopoiesis as a predictive marker for development of therapy-related myeloid neoplasia (t-MN) following neoadjuvant therapy for breast cancer: a Southwest Oncology Group study (S0012).
Marilyn L Slovak, Victoria Bedell, +8 authors, Wendy Stock.
Breast Cancer Res Treat, 2009 Oct 24; 119(2). PMID: 19851858    Free PMC article.
Secondary malignancies across the age spectrum.
Andrea K Ng, Lisa B Kenney, Ethel S Gilbert, Lois B Travis.
Semin Radiat Oncol, 2009 Dec 05; 20(1). PMID: 19959033    Free PMC article.
Review.
Drug-induced hematologic syndromes.
David M Mintzer, Shira N Billet, Lauren Chmielewski.
Adv Hematol, 2009 Dec 05; 2009. PMID: 19960059    Free PMC article.
Outcome of allo-SCT for women with MDS or AML occurring after breast cancer therapy.
P Armand, H T Kim, +6 authors, R J Soiffer.
Bone Marrow Transplant, 2010 Feb 16; 45(11). PMID: 20154738    Free PMC article.
The Role of Supportive Therapy in the Era of Modern Adjuvant Treatment - Current and Future Tools.
Rupert Bartsch, Guenther G Steger.
Breast Care (Basel), 2009 Jan 01; 4(3). PMID: 20847876    Free PMC article.
Therapy-related acute leukemia in breast cancer patients: twelve cases treated with a topoisomerase inhibitor.
Hyoeun Shim, Hyun-Sook Chi, +5 authors, Kyoo-Hyung Lee.
Korean J Hematol, 2010 Dec 02; 45(3). PMID: 21120206    Free PMC article.
Early breast cancer in the older woman.
Sonal Gandhi, Sunil Verma.
Oncologist, 2011 Mar 19; 16(4). PMID: 21415085    Free PMC article.
Review.
Congenital neutropenia: diagnosis, molecular bases and patient management.
Jean Donadieu, Odile Fenneteau, +2 authors, Christine Bellanné Chantelot.
Orphanet J Rare Dis, 2011 May 21; 6. PMID: 21595885    Free PMC article.
Review.
Increased incidence of myelodysplastic syndrome and acute myeloid leukemia following breast cancer treatment with radiation alone or combined with chemotherapy: a registry cohort analysis 1990-2005.
Henry G Kaplan, Judith A Malmgren, Mary K Atwood.
BMC Cancer, 2011 Jun 23; 11. PMID: 21693006    Free PMC article.
Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms.
Hilda Rachel Diamond, Maria Helena Ornellas, +11 authors, Eliana Abdelhay.
J Hematol Oncol, 2011 Sep 29; 4. PMID: 21951951    Free PMC article.
Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results.
Banu K Arun, Kapil Dhinghra, +16 authors, Gabriel N Hortobagyi.
Oncologist, 2011 Nov 02; 16(11). PMID: 22042783    Free PMC article.
Second malignancies among elderly survivors of cancer.
Ari M VanderWalde, Arti Hurria.
Oncologist, 2011 Nov 02; 16(11). PMID: 22042787    Free PMC article.
Review.
The cost-utility of adjuvant chemotherapy using docetaxel and cyclophosphamide compared with doxorubicin and cyclophosphamide in breast cancer.
T Younis, D Rayson, C Skedgel.
Curr Oncol, 2011 Dec 21; 18(6). PMID: 22184496    Free PMC article.
Incidence of acute myeloid leukemia after breast cancer.
Caterina Giovanna Valentini, Luana Fianchi, +3 authors, Livio Pagano.
Mediterr J Hematol Infect Dis, 2012 Jan 06; 3(1). PMID: 22220266    Free PMC article.
A way forward on the medically appropriate use of white cell growth factors.
Thomas J Smith, Bruce E Hillner.
J Clin Oncol, 2012 Mar 01; 30(14). PMID: 22370327    Free PMC article.
Review.
Risk of second cancer after initial treatment of breast cancer: An Osaka Cancer Registry Database study.
Yumi Kamigaki, Koji Kawakami.
Oncol Lett, 2012 Aug 07; 2(5). PMID: 22866158    Free PMC article.
What's all the fuss about? facts and figures about bone marrow failure and conditions.
Sudipto Mukherjee, Mikkael A Sekeres.
Curr Hematol Malig Rep, 2012 Sep 01; 7(4). PMID: 22936422
Review.
The use of biomonitoring data in exposure and human health risk assessment: benzene case study.
Scott M Arnold, Juergen Angerer, +4 authors, A Robert Schnatter.
Crit Rev Toxicol, 2013 Jan 26; 43(2). PMID: 23346981    Free PMC article.
Review.
Mutational analysis of therapy-related myelodysplastic syndromes and acute myelogenous leukemia.
Alan H Shih, Stephen S Chung, +6 authors, Virginia M Klimek.
Haematologica, 2013 Jan 26; 98(6). PMID: 23349305    Free PMC article.
Colony-stimulating factors for febrile neutropenia during cancer therapy.
Charles L Bennett, Benjamin Djulbegovic, LeAnn B Norris, James O Armitage.
N Engl J Med, 2013 Mar 22; 368(12). PMID: 23514290    Free PMC article.
Review.
Neoadjuvant chemotherapy and targeted therapy in breast cancer: past, present, and future.
Simon P Gampenrieder, Gabriel Rinnerthaler, Richard Greil.
J Oncol, 2013 Sep 13; 2013. PMID: 24027583    Free PMC article.
Review.
Chemotherapy causes cancer! A case report of therapy related acute myeloid leukaemia in early stage breast cancer.
J Cole Aidan, Nicole R Priddee, James J McAleer.
Ulster Med J, 2013 Oct 02; 82(2). PMID: 24082288    Free PMC article.
Review.
Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors.
Hui Lin Chua, P Artur Plett, +5 authors, Christie M Orschell.
Health Phys, 2013 Nov 28; 106(1). PMID: 24276547    Free PMC article.
The evolving challenge of therapy-related myeloid neoplasms.
Jane E Churpek, Richard A Larson.
Best Pract Res Clin Haematol, 2014 Feb 11; 26(4). PMID: 24507808    Free PMC article.
Review.
Second malignancies after breast cancer: The impact of adjuvant therapy.
Chunhui Dong, Ling Chen.
Mol Clin Oncol, 2014 Apr 29; 2(3). PMID: 24772296    Free PMC article.
Review.
Risk of hospitalization according to chemotherapy regimen in early-stage breast cancer.
Carlos H Barcenas, Jiangong Niu, +6 authors, Sharon H Giordano.
J Clin Oncol, 2014 May 29; 32(19). PMID: 24868022    Free PMC article.
Adjuvant chemotherapy in breast cancer: To use or not to use, the anthracyclines.
Jennifer A Crozier, Abhisek Swaika, Alvaro Moreno-Aspitia.
World J Clin Oncol, 2014 Aug 13; 5(3). PMID: 25114866    Free PMC article.
Review.
Update on adjuvant chemotherapy for early breast cancer.
Murtuza M Rampurwala, Gabrielle B Rocque, Mark E Burkard.
Breast Cancer (Auckl), 2014 Oct 23; 8. PMID: 25336961    Free PMC article.
Review.
Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience.
Antonio C Wolff, Amanda L Blackford, +10 authors, Judith E Karp.
J Clin Oncol, 2014 Dec 24; 33(4). PMID: 25534386    Free PMC article.
Evaluation of Peripheral Blood Smear for Myelodysplasia in Breast Cancer Patients who Received Adjuvant Antracycline.
Hasan Mutlu, Zeki Akca, Havva Uskudar Teke, Hediye Ugur.
Eurasian J Med, 2011 Dec 01; 43(3). PMID: 25610187    Free PMC article.
Breast cancer survivorship: a comprehensive review of long-term medical issues and lifestyle recommendations.
Balazs I Bodai, Phillip Tuso.
Perm J, 2015 Apr 23; 19(2). PMID: 25902343    Free PMC article.
Review.
Radiotherapy- and chemotherapy-induced myelodysplasia syndrome: a nationwide population-based nested case-control study.
Li-Min Sun, Cheng-Li Lin, +2 authors, Chia-Hung Kao.
Medicine (Baltimore), 2015 May 02; 94(17). PMID: 25929909    Free PMC article.
Racial and ethnic differences in risk of second primary cancers among breast cancer survivors.
Gregory S Calip, Ernest H Law, Naomi Y Ko.
Breast Cancer Res Treat, 2015 May 28; 151(3). PMID: 26012645    Free PMC article.
Current knowledge and future research directions in treatment-related second primary malignancies.
Lindsay M Morton, Anthony J Swerdlow, +4 authors, Flora E van Leeuwen.
EJC Suppl, 2015 Jul 29; 12(1). PMID: 26217162    Free PMC article.
Myelodysplastic syndrome and acute myeloid leukemia following adjuvant chemotherapy with and without granulocyte colony-stimulating factors for breast cancer.
Gregory S Calip, Judith A Malmgren, +2 authors, Henry G Kaplan.
Breast Cancer Res Treat, 2015 Oct 10; 154(1). PMID: 26450505    Free PMC article.
Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age.
Sandra M Swain, Raquel Nunes, +2 authors, Amy P Sing.
Adv Ther, 2015 Nov 28; 32(12). PMID: 26610382    Free PMC article.
Long-term Toxicity of Cancer Treatment in Older Patients.
Armin Shahrokni, Abraham J Wu, Jeanne Carter, Stuart M Lichtman.
Clin Geriatr Med, 2015 Nov 29; 32(1). PMID: 26614861    Free PMC article.
Review.
Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia.
Jane E Churpek, Rafael Marquez, +13 authors, Richard A Larson.
Cancer, 2015 Dec 08; 122(2). PMID: 26641009    Free PMC article.
How breast cancer chemotherapy increases the risk of leukemia: Thoughts about a case of diffuse large B-cell lymphoma and leukemia after breast cancer chemotherapy.
Bin Zhang, Xia Zhang, +3 authors, Jinming Yu.
Cancer Biol Ther, 2016 Feb 11; 17(2). PMID: 26861804    Free PMC article.
Cost-effectiveness and resource use of implementing MRI-guided NACT in ER-positive/HER2-negative breast cancers in The Netherlands.
Anna Miquel-Cases, Lotte M G Steuten, Lisanne S Rigter, Wim H van Harten.
BMC Cancer, 2016 Sep 07; 16. PMID: 27595620    Free PMC article.
Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality.
Lin Li, Xiaotian Qi, +12 authors, Lingtao Wu.
EMBO Mol Med, 2016 Nov 04; 8(11). PMID: 27737899    Free PMC article.
Risk of acute myeloid leukemia and myelodysplastic syndrome among older women receiving anthracycline-based adjuvant chemotherapy for breast cancer on Modern Cooperative Group Trials (Alliance A151511).
Rachel A Freedman, D K Seisler, +17 authors, H B Muss.
Breast Cancer Res Treat, 2016 Nov 21; 161(2). PMID: 27866278    Free PMC article.
Post-Transplantation Cyclophosphamide after Bone Marrow Transplantation Is Not Associated with an Increased Risk of Donor-Derived Malignancy.
Robbie G Majzner, Huzefa Mogri, +11 authors, Heather J Symons.
Biol Blood Marrow Transplant, 2017 Jan 08; 23(4). PMID: 28062216    Free PMC article.
Molecular signature of anastasis for reversal of apoptosis.
Ho Man Tang, C Conover Talbot, Ming Chiu Fung, Ho Lam Tang.
F1000Res, 2017 Mar 30; 6. PMID: 28299189    Free PMC article.
Risk of myeloid neoplasms after radiotherapy among older women with localized breast cancer: A population-based study.
Amer M Zeidan, Jessica B Long, +10 authors, Amy J Davidoff.
PLoS One, 2017 Sep 14; 12(9). PMID: 28902882    Free PMC article.
The Toll-Like Receptor 2/6 Agonist, FSL-1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome.
Cathryn J Kurkjian, Hao Guo, +6 authors, Jenny P-Y Ting.
Sci Rep, 2017 Dec 13; 7(1). PMID: 29230065    Free PMC article.
Detecting Anastasis In Vivo by CaspaseTracker Biosensor.
Ho Man Tang, Ming Chiu Fung, Ho Lam Tang.
J Vis Exp, 2018 Feb 15; (132). PMID: 29443051    Free PMC article.
Lung cancer induced from chemotherapy a 20 years old case.
Konstantinos Sapalidis, Stella Laskou, +16 authors, Isaak Kesisoglou.
Respir Med Case Rep, 2018 Jul 07; 24. PMID: 29977753    Free PMC article.
Myeloid Leukemias: A Glance at Middle Eastern Centers.
Safaa Aa Khaled, Ola Nabih, Nashwa M Abdel Aziz, Dalia G Mahran.
J Blood Med, 2020 Jan 08; 10. PMID: 31908557    Free PMC article.
Reducing the toxicity of cancer therapy: recognizing needs, taking action.
Charles S Cleeland, Jeff D Allen, +7 authors, Jamey Skillings.
Nat Rev Clin Oncol, 2012 Jul 04; 9(8). PMID: 22751283
Review.
Evaluation of the Incidence of Hematologic Malignant Neoplasms Among Breast Cancer Survivors in France.
Marie Joelle Jabagi, Norbert Vey, +3 authors, Rosemary Dray-Spira.
JAMA Netw Open, 2019 Jan 19; 2(1). PMID: 30657534    Free PMC article.
Anastasis: recovery from the brink of cell death.
Ho Man Tang, Ho Lam Tang.
R Soc Open Sci, 2019 Mar 07; 5(9). PMID: 30839720    Free PMC article.
Review.
Maximizing Breast Cancer Therapy with Awareness of Potential Treatment-Related Blood Disorders.
Henry G Kaplan, Gregory S Calip, Judith A Malmgren.
Oncologist, 2020 Feb 20; 25(5). PMID: 32073195    Free PMC article.
Review.
Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia.
HeeJin Cheon, Karolina H Dziewulska, +4 authors, Thomas P Loughran.
Curr Hematol Malig Rep, 2020 Feb 18; 15(2). PMID: 32062772    Free PMC article.
Review.
Uncoupling DNA damage from chromatin damage to detoxify doxorubicin.
Xiaohang Qiao, Sabina Y van der Zanden, +24 authors, Jacques Neefjes.
Proc Natl Acad Sci U S A, 2020 Jun 20; 117(26). PMID: 32554494    Free PMC article.
The prophylactic and therapeutic effects of moxibustion combined with traditional Chinese medicine decoction for treating chemotherapy-induced myelosuppression in early-stage breast cancer: study protocol for a randomized controlled trial.
Yajie Ji, Siyu Li, +19 authors, Xiaohong Xue.
Trials, 2020 Oct 14; 21(1). PMID: 33046128    Free PMC article.
Use of white blood cell growth factors and risk of acute myeloid leukemia or myelodysplastic syndrome among elderly patients with non-Hodgkin lymphoma.
Stephen K Gruschkus, David Lairson, +2 authors, Xianglin L Du.
Cancer, 2010 Jul 29; 116(22). PMID: 20665502    Free PMC article.
Clinical utilization of long-acting granulocyte colony-stimulating factor (pegfilgrastim) prophylaxis in breast cancer patients with adjuvant docetaxel-cyclophosphamide chemotherapy.
Ye Won Jeon, Seung Taek Lim, +4 authors, Young Jin Suh.
Ann Surg Treat Res, 2021 Feb 16; 100(2). PMID: 33585350    Free PMC article.
Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors.
Konstantinos V Floros, Sheeba Jacob, +8 authors, Anthony C Faber.
Cell Death Dis, 2021 Feb 17; 12(2). PMID: 33589591    Free PMC article.