Clinical Significance of Additional Cytogenetic Abnormalities (ACA) at Disease Progression in Patients with High-Risk Myelodysplastic Syndrome (MDS) Treated with Azacitidine

Background: Although cytogenetic abnormalities at diagnosis are recognized as one of the most important prognostic factors in MDS patients, their cytogenetic findings are not stable and ACA are sometimes acquired in their clinical courses. We recently described that ACA acquisition at relapse was found in 40% and associated with the lower second complete remission (CR) rate and the inferior overall survival (OS) rate in adult patients with acute myeloid leukemia (AML) and Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL). However, this clinical impact of ACA acquisition has not been elucidated in high-risk MDS patients during azacitidine treatment. So, we conducted this retrospective study to address this unsolved issue. Patients and methods: Of the 63 patients who were diagnosed as high-risk MDS according to French-American-British classification and were treated with azacitidine between 2012 and 2019, 34 whose cytogenetic data both at diagnosis and disease progression were available were included in this study. Treatment response to azacitidine was evaluated based on international working group response criteria for myelodysplasia. Cytogenetic changes between the time of diagnosis and disease progression were classified into four groups: (1) no change, (2) ACA was acquired at time of disease progression, (3) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared at the time of disease progression, and (4) cytogenetic abnormalities observed at diagnosis were reduced or had disappeared, and completely different ACA was acquired at the time of disease progression. In this study, groups 2 and 4 were defined as those with ACA acquisition. OS was defined as the interval from the date of disease progression 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. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. The potential factors evaluated in this analysis were age, gender, blast count in bone marrow (< or => 10%), karyotype (complex or not), revised international prognostic scoring sysytem (high/high-intermediate or not), and response to azacitidine (CR/partial remission or not). Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 34 patients included in this study, 25 were male and 9 were female, and the median age was 66 years (range, 38-78 years). According to the definition described above regarding cytogenetic changes between the time of diagnosis and disease progression, 11 (32%), 14 (41%), 0 (0%), and 9 (26%) patients were categorized into group 1, 2, 3, and 4, respectively; thus, 23 patients (67%) acquired ACA at disease progression with a higher incidence in comparison with that of AML and Ph-negative ALL patients. In univariate analysis, only complex karyotype at treatment initiation was extracted as a significant predisposing factor for ACA acquisition at disease progression (100% vs. 47.6%, respectively; p = 0.002). Among 14 patients (nine and five in patients with and without ACA acquisition, respectively) received chemotherapy after disease progression, only two (14.3%) achieved CR (one and one, respectively). Although the OS rates after disease progression were not significantly different between patients with and without ACA acquisition (19.3% vs. 32.0% at one year, respectively; p = 0.256), in multivariate analysis, only ACA acquisition was identified as a negative prognostic factor of OS after disease progression (hazard ratio: 3.21, p = 0.043). Conclusion: These findings suggested that ACA acquisition at disease progression is frequently observed in high-risk MDS patients treated with azacitidine, especially in those harboring complex karyotype, and is associated with poor prognosis even after azacitidine failure, just like AML and Ph-negative ALL. As clinical impacts of ACA acquisition are common among multiple hematologic malignancies, to clarify the biological basis of ACA acquisition might contribute to the development of novel therapeutic strategies.