Acute Myeloid Leukemia and Myelodysplastic Syndrome After Doxorubicin-Cyclophosphamide Adjuvant Therapy for Operable Breast Cancer: The National Surgical Adjuvant Breast and Bowel Project Experience

2003 ◽  
Vol 21 (7) ◽  
pp. 1195-1204 ◽  
Author(s):  
Roy E. Smith ◽  
John Bryant ◽  
Arthur DeCillis ◽  
Stewart Anderson
Keyword(s):  
Breast Cancer ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Incidence Rates ◽  
Breast Radiotherapy ◽  
Increased Risk ◽  
Breast Cancer Relapse ◽  
Acute Myeloid

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/m2 q 21 days × 4. C was given as follows: 600 mg/m2 q 21 days × 4 (“standard AC”); 1,200 mg2 q 21 days × 2; 1,200 mg/m2 q 21 days × 4; 2,400 mg/m2 q 21 days × 2; and 2,400 mg/m2 q 21 days × 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/m2 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.

Allogeneic Stem Cell Transplantation (allo-SCT) for Secondary Acute Myeloid Leukemia (AML) Following Breast Carcinoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3305-3305
Author(s):  
Sameh Ayari ◽  
Mohamad Mohty ◽  
Karin Bilger ◽  
Gaelle Guillerm ◽  
Denis Guyotat ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Breast Carcinoma ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Acute Myeloid

Abstract Abstract 3305 Poster Board III-193 Patients with breast carcinoma who received Radio and/or chemotherapy, have an increased risk for developing therapy-related myelodysplastic syndromes/acute myeloid leukemia (1-5%). Such secondary AMLs have often poor prognosis when treated with conventional chemotherapy. This retrospective series assessed the outcome of 29 female patients who were reported to the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire Registry, and who were treated with allo-SCT for secondary MDS/AML developing after initial therapy for breast cancer. The median age of patients at time of breast cancer treatment was 51 (range, 31-62) years. The median age at time of allo-SCT was 53 (range 31-63) years. Diagnosis included 21 AML and 8 MDS. Cytogenetics: four patients had CBF abnormalities, 10 had 11q23 abnormalities, 5 had an intermediate caryotype and 3 had unfavourable one. At time of allo-SCT, 21 patients were in complete remission (CR), while 8 had a refractory/relapsed disease. PBSCs were used as stem cell source in 18 patients, while 9 patients received classical bone marrow and one patient received an unrelated umbilical cord blood. Patients received a median of 5.2 ×10e6/Kg CD34+ cells. A matched related donor was used in 23 cases (82%) and an unrelated donor in 5 cases (18%). Conditioning regimen was myeloablative (Cy-TBI or Bu-Cy) in 7 cases (24%) and reduced-intensity in 22 cases (76%). Twenty four patients engrafted with a median time of 18 (range, 9-32) days for ANC>500/μL. Seven (24%) patients experienced grade 2-4 acute GVHD. Also, 7 patients (24%) experienced chronic GVHD (5 extensive and 2 limited). With a median follow-up of 24 (range, 3-129) months, 16 patients (55%) were still alive. Disease progression accounted for 6 deaths while transplant related causes (infection n=4, GVHD n=1, MOF n=1, cardiac failure n=1) occurred in 7 cases. The Kaplan-Meier estimates of overall and disease-free survival at 2 years were at 54 and 38% respectively. These results highlight the poor outcome of secondary leukemia occurring after therapy for breast cancer, even with the use of allo-SCT. Innovative maintenance approaches such as early use of hypomethylating or immunomodulatory agents after allo-SCT aiming to decrease the relapse are warranted. Disclosures No relevant conflicts of interest to declare.

Risk of Acute Myeloid Leukemia and Myelodysplastic Syndrome in Trials of Adjuvant Epirubicin for Early Breast Cancer: Correlation With Doses of Epirubicin and Cyclophosphamide

2005 ◽  
Vol 23 (18) ◽  
pp. 4179-4191 ◽  
Author(s):  
Claudio Praga ◽  
Jonas Bergh ◽  
Judith Bliss ◽  
Jacques Bonneterre ◽  
Bruno Cesana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Early Breast Cancer ◽  
Myeloid Leukemia ◽  
Lower Probability ◽  
Cumulative Probability ◽  
Secondary Leukemia ◽  
Acute Myeloid

Purpose We reviewed follow-up of patients treated in 19 randomized trials of adjuvant epirubicin in early breast cancer to determine incidence, risk, and risk factors for subsequent acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Patients and Methods The patients (N = 9,796) were observed from the start of adjuvant treatment (53,080 patient-years). Cases of AML or MDS (AML/MDS) were reported, with disease characteristics. Incidence and cumulative risk were compared for possible risk factors, for assigned regimens, and for administered cumulative doses of epirubicin and cyclophosphamide. Results In 7,110 patients treated with epirubicin-containing regimens (92% of whom also received cyclophosphamide), 8-year cumulative probability of AML/MDS was 0.55% (95% CI, 0.33% to 0.78%). The risk of developing AML/MDS increased in relation to planned epirubicin dose per cycle, planned epirubicin dose-intensity, and administered cumulative doses of epirubicin and cyclophosphamide. Patients with administered cumulative doses of both epirubicin and cyclophosphamide not exceeding those used in standard regimens (≤ 720 mg/m2 and ≤ 6,300 mg/m2, respectively) had an 8-year cumulative probability of developing AML/MDS of 0.37% (95% CI, 0.13% to 0.61%) compared with 4.97% (95% CI, 2.06% to 7.87%) for patients administered higher cumulative doses of both epirubicin and cyclophosphamide. Conclusion Patients treated with standard cumulative doses of adjuvant epirubicin (≤ 720 mg/m2) and cyclophosphamide (≤ 6,300 mg/m2) for early breast cancer have a lower probability of secondary leukemia than patients treated with higher cumulative doses. Increased risk of secondary leukemia must be considered when assessing the potential benefit to risk ratio of higher than standard doses.

Defective DNA mismatch repair in acute myeloid leukemia/myelodysplastic syndrome after organ transplantation

Blood ◽  
2004 ◽  
Vol 104 (3) ◽  
pp. 822-828 ◽  
Author(s):  
Judith Offman ◽  
Gerhard Opelz ◽  
Bernd Doehler ◽  
David Cummins ◽  
Ozay Halil ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myelodysplastic Syndrome ◽  
Mismatch Repair ◽  
Organ Transplantation ◽  
Myeloid Leukemia ◽  
Dna Mismatch Repair ◽  
Dna Mismatch ◽  
Increased Risk ◽  
Acute Myeloid

AbstractImmunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.

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