Clinical Outcome of Therapy-Related Acute Myeloid Leukemia Is Strongly Related to Cytogenetic Analysis

Background:

Treatment-related AML (t-AML) accounts for 10 to 20% of all AML cases and carries an especially poor prognosis (Kayser et al. 2011, Godley et al. 2008).  Patients diagnosed with t-AML are likely to have abnormal cytogenetic profiles with chromosome changes that are predictive of an aggressive malignancy, poor response to therapy, and decreased overall survival (Smith et al.2003).  The simultaneous use of multiple chemotherapeutic agents of different classes makes it increasingly difficult to predict risk for developing t-AML and determining disease course.  An updated analysis of predictive factors for t-AML is needed so clinicians can more accurately inform patients of their prognosis.  The aim of this study was to classify t-AML according to primary malignancy, previous chemotherapy exposure, and cytogenetic profile.

Methods:

A retrospective chart review of patients that were diagnosed with AML at Mayo Clinic from 7/1/1990 to 5/13/2015 was performed following IRB approval.  AML patients found to have a previous malignancy treated with chemotherapy were classified as t-AML. Chemotherapeutics were classified as alkylating agents, antimetabolites, anti-tubulin agents, and topoisomerase II inhibitors. Patients diagnosed with a myelodysplastic or myeloproliferative disorder prior to development of AML were excluded from this study.  Previous chemotherapy exposures, duration of chemotherapy exposure, complete blood count, chromosome abnormalities, and survival data were collected for t-AML cases.  Cytogenetic changes were classified as favorable, intermediate, and adverse according to the system used by Kayser et al. 2011.  JMP 10.0 was used for statistical analysis.

Results: 

Out of 584 patients, 64 patients (11%) had a primary malignancy that was treated with chemotherapy prior to being diagnosed with AML.  The most common primary malignancies were breast cancer (31%), non-Hodgkin lymphoma (27%), colorectal cancer (8%), and Hodgkin lymphoma (8%).  Laboratory findings showed median hemoglobin 9.6 g/dL (4.7-13.8), median white blood cells 3.2 x10⁹ (0.6-126), median platelets 50 x10⁹ (3-320), median peripheral blood blasts of 8% (0-91), and median bone marrow blasts 38% (1-94).  95% of patients diagnosed with t-AML had been previously treated with an alkylating agent.  Additional exposure to an anti-metabolite trended towards a more adverse cytogenetic profile (χ²=5.0, p=0.08) but there was not a statistically significant decrease in overall survival (KM analysis, p=0.31). 

The median overall survival for patients diagnosed with t-AML was 10.2 months compared to 19.2 months for patients with de-novo AML (KM analysis, p=0.04).  Adverse cytogenetic profiles were associated with decreased survival (KM analysis, p <0.0001).  However, there was no difference in overall survival between patients with t-AML that had intermediate cytogenetics and those with de-novo AML (KM analysis, p=0.36).  None of the chemotherapy classes other than antimetabolites were associated with poor cytogenetics or survival when combined with an alkylating agent.

Conclusion:

Over half of all patients classified as having t-AML in this study received prior chemotherapy for breast cancer or non-Hodgkin lymphoma. Cytogenetic classification of t-AML into favorable, intermediate and adverse groups is useful in predicting disease course.  Interestingly, t-AML patients with intermediate risk cytogenetics had similar overall survival to patients with de-novo AML.  This suggests that the poor outcomes observed in patients with t-AML is predominantly due to the subset with adverse cytogenetics.  Thus, cytogenetic analysis remains the best indicator of overall survival regardless of chemotherapy exposure.  Additional work is needed to delineate the risk associated with the aforementioned chemotherapy classes.