Clinical Significance of Additional Cytogenetic Abnormalities (ACA) Acquired at the First Relapse in Adult Acute Myeloid Leukemia (AML) Patients
Authors: Shimizu Hiroaki , Yokohama Akihiko , Hatsumi Nahoko , Takada Satoru , Saitoh Takayuki , Handa Hiroshi , Sakura Toru , Nojima Yoshihisa 
Published: October 2019

Abstract
Background: Cytogenetic changes between the time of diagnosis and the first relapse are found in 30 to 60% of relapsed AML cases. ACA, the most frequent form of cytogenetic changes, are considered as a result of genetic instability and clonal evolution of AML cells. However, because the clinical significance of ACA has not been elucidated in adult AML patients, we conducted a large-scale retrospective study to address this unsolved issue.
Patients and methods: Of the 375 adult patients diagnosed with AML between 1990 and 2010, 144 relapsed patients whose cytogenetic abnormality data both at diagnosis and at the first relapse were available were included in this study. All these patients underwent intensive chemotherapy. Patients with acute promyelocytic leukemia were excluded. Cytogenetic changes between the time of diagnosis and the first relapse were classified into four groups: (1) no change, (2) ACA was acquired at time of the first relapse, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of the first relapse, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of the first relapse. In this study, groups 2 and 4 were defined as those with ACA acquisition. Overall survival (OS) was defined as the interval from the date of the first relapse to the date of death. Fisher’s exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Multiple logistic regression analysis and the Cox proportional hazard model were used for multivariate analysis of predisposing factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance.
Results: Of the 144 patients included in this study, 81 patients were male, and 63 were female. The median age was 53 years (range, 15–79 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and the first relapse, 83 (58%), 55 (38%), 2 (1%), and 4 (3%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 59 patients (41%) acquired ACA at the first relapse. With univariate analysis, t(8;21), complex karyotype, fewer than 12 months duration of the first remission, and relapse after allogeneic stem cell transplantation (allo-SCT) were extracted as statistically significant predisposing factors for ACA acquisition at the first relapse. Of these four factors, the first three were confirmed with multivariate analysis to be independent predisposing factors. Excluding four patients that directly proceeded to allo-SCT without re-induction chemotherapy, the 140 patients with ACA acquisition showed a significantly lower second remission rate compared with those without ACA acquisition (20.0% vs. 72.5%, respectively; p < 0.001). Furthermore, among all 144 patients, the 3-year OS rate after the first relapse in patients with ACA acquisition was significantly poorer than that in those without ACA acquisition (8.5% vs. 36.8%, respectively; p < 0.001). Multivariate analysis revealed that ACA acquisition was the strongest negative prognostic factor compared to all other reported factors (hazard ratio: 2.13, p < 0.001). Of the 59 patients with ACA acquisition (median age: 51, range; 15–79 years), 27 underwent allo-SCT after the first relapse. Eight patients were in remission at the time of transplant, and one directly proceeded to allo-SCT without re-induction chemotherapy. The 3-year OS rates after the first relapse were significantly different between patients undergoing allo-SCT after the first relapse and those treated only with chemotherapy (17.8% vs. 0%; p = 0.007). With multivariate analysis, undergoing allo-SCT after the first relapse was identified as an independent prognostic factor, in addition to the cytogenetic risk group at diagnosis.
Conclusion: These findings suggested that ACA acquisition at the time of the first relapse was associated with chemo-refractive disease and poor prognosis. As ACA acquisition showed the most potent prognostic impact, treatment approaches for relapsed AML patients should be determined with consideration of this phenomenon. Clarification of the biological background of ACA acquisition may contribute to the development of novel therapeutic strategies and improved treatment outcomes in adult AML patients.

Disclosures
No relevant conflicts of interest to declare.