Therapy-Related Myelodysplasia/Acute Myeloid Leukemia (t-MDS/AML) After Conventionally-Treated Breast Cancer: Impact of Cytogenetics on Outcome After Allogeneic Hematopoietic Cell Transplantation (HCT),
Authors: Grover Rajinder S. , Pullarkat Vinod , Sun Can-Lan , Bhatia Smita , Forman Stephen J. 
Published: October 2019

Abstract 4149

Background:
The outcome of early stage breast cancer has improved in recent years with use of effective combination chemotherapy, including cyclophosphamide, anthracyclines or taxanes. Patients who undergo lumpectomy also receive radiation therapy for locoregional control. t-MDS/AML are rare but serious consequences of these therapeutic exposures; historically with an overall poor prognosis. Translocations involving the mixed-lineage leukemia (MLL) gene on chromosome band 11q23, and core binding factor genes on 21q22 and 16q22, are hallmarks of t-MDS/AML resulting from treatment with topoisomerase II inhibitors (anthracyclines). Loss of part or whole of chromosomes 5 and/or 7 (5-/7- abnormality) are associated with t-MDS/AML after treatment with alkylating agents and radiation. Allogeneic HCT (sibling-related, unrelated or double-cord) offers the only curative option for some of these patients. However, the long-term outcome of post-breast cancer t-MDS/AML after allogeneic HCT has not been described, and subgroups with better or worse prognosis not identified.

Methods:
From 1997 to 2011, 28 patients with t-MDS/AML after treatment of breast cancer with conventional chemotherapy and/or radiation underwent allogeneic HCT at City of Hope. Overall survival defined from the time of allogeneic HCT to the last date of follow up or date of death, was estimated using Kaplan-Meier method. Cox regression techniques were utilized to understand predictors of overall survival.

Results:
Of the 28 patients, 16 had been treated for early-stage breast cancer (I/IIA), 11 had received treatment for locally advanced disease (IIB/ III) and 1 patient had metastatic disease. Twenty-five patients received combination chemotherapy as adjuvant therapy or for metastatic disease; this included cyclophosphamide (100%), doxorubicin (88%) and taxanes (52%). Details of chemotherapy are unknown for one patient. Twenty-one patients (75%) also received radiation (2 received radiation alone). Median age at time of diagnosis of t-MDS/AML was 56 years (range: 34–79); median time from diagnosis of breast cancer to diagnosis of t-MDS/AML was 2.4 years (range 1–12.3); median time from t-MDS/AML to allogeneic HCT was 0.55 year (range: 0.15–4.1). Ten patients presented with MDS and 18 with AML. Cytogenetic abnormalities included MLL - 11q23 abnormality (n=12), 5-/7- and/or complex abnormalities (n=9), t(15;17)(q22;q21.1) (n=1), t(8;21) (n=1), inv(16)(p13.1;q22) (n=2). Of the 28 patients, 27 were treated with induction therapy and 74% were in complete remission (CR) at the time of HCT. Fourteen patients (50%) received sibling-related HCT, 13 received matched unrelated donor (MUD) transplant and 1 received a double cord transplant. Two patients received second allogeneic HCT and one patient received donor lymphocyte infusion (DLI) for relapsed t-MDS/AML. Sixty-one percent received reduced-intensity conditioning with fludarabine/melphalan and others received full-intensity conditioning. Sixteen patients developed cGvHD after transplant. After a median follow up of 2.2 years, 8 patients had died (cause of death: t-MDS/AML [n=5], sepsis [n=1], GvHD [n=1], breast cancer [n=1]), with an overall survival of 78.2% at two years post-HCT for the entire cohort. The 2-year overall survival was 71.4% for sibling-related HCT and 84.4% for MUD (log-rank p=0.14). There was a difference in overall survival by the type of cytogenetic abnormalities. Thus, the 2-year survival rate for patients with 11q23 abnormality was 90.9% while that for patients with chromosome 5-/7- abnormalities or complex abnormalities was 62.5% (log rank p=0.27). Patients with cGvHD had better outcome compared with those without cGvHD (2 year survival 87.5% vs. 64.3%, log-rank p value=0.03). These findings were confirmed on multivariate regression analysis, which revealed chromosome 5-/7- or complex abnormalities to be associated with a significantly worse outcome (HR=6.9, p=0.035), while cGvHD was associated with a better outcome (HR=0.14, p=0.02) after adjustment for age at HCT.

Conclusions:
Although t-MDS/AML after conventional treatment of breast cancer has historically been shown to have a poor prognosis, allogeneic HCT in patients with available donors provides a chance of cure. Among patients undergoing allogeneic HCT, a superior outcome was observed in patients with 11q23 abnormalities and among those with cGvHD.

Disclosures:
No relevant conflicts of interest to declare.