Changes in the Pattern of Cytogenetic Aberrations with Advancing Age in Acute Myeloid (Non-APL) Leukemia: A Southwest Oncology Study (S9007).
Authors: Norwood Thomas H. , Gundacker Holly M. , Slovak Marilyn L. , Erba Harry Paul , Appelbaum Frederick R. 
Published: April 2020

It is well known that, with advancing age, diseases and clinical procedures are associated with increased morbidity and mortality. This increasing vulnerability in the elderly with acute myeloid leukemia has been documented in a previous report of a study of a group of patients enrolled in five Southwest Oncology Group (SWOG) studies (Appelbaum, et al., Blood, 2006 May 1;107(9):3481-6). The authors of that study observed that the frequency of unfavorable risk cytogenetics was significantly elevated in patients over the age of 75. In this study we have examined the nature of cytogenetic changes over the entire adult life span in greater detail. We included the same patient population noted above plus additional AML patients with eligible cytogenetics data registered on a cytogenetics ancillary study SWOG 8750/9007, including a recent treatment study with subjects over the age of 70 years (S0432). A total of 1069 patients from 10 SWOG therapeutic clinical trials of previously untreated AML were included in this analysis. The abnormalities detected in this study are consistent with the emergence of increased genomic instability in the malignant clone. We observed an increasing frequency of complex karyotypes in the older subjects. For each 10 years increase in age there was a 16% increase (95% confidence interval 14%–19%) in the average number or abnormalities per individual, which was statistically significant (Poisson regression model, P&lt;0.0001). The frequency of homogeneously staining regions and double minutes, cytogenetic evidence of gene amplification, progressively increased in patients in the fifth to the eighth decade (logistic regression model P&lt;0.016). A similar increase was observed in the frequency of isochromosome formation. The breakpoints in the structural aberrations tended to cluster in specific regions of the karyotype. This clustering was more pronounced in the karyotypes from the older patients with significant increases most evident in bands 7q22 and 12p13 (logistic regression model P = 0.0073). For patients less than 60 years of age, 4% have a loss of chromosome 17 or 18 compared to 13% of patients 60 years or older (logistic regression model P = 0.0001). The total number of identifiable chromosomes lost and gained also significantly increased with age (Poisson regression model P values &lt; 0.0001 and = 0.001, respectively). An increase in the frequency of marker chromosome formation with age correlated with the total chromosome loss (Spearman rank correlation P = 0.0001). These results suggest that the numerical changes that occur with advancing age can be accounted for by both mitotic instability and the degradation of identifiable chromosomes into marker chromosomes. These findings are consistent with the notion that the increased severity of acute myeloid leukemia in elderly patients is, in addition to the increased vulnerability associated with aging phenotype, also due to a pathogenetic progression that is distinct from that present in most younger leukemic patients.