Clinical and Prognostic Significance of Additional Chromosomal Abnormalities at Diagnosis of Chronic Myeloid Leukemia
Authors: Jiří Mayer, Petra Čičátková, Lenka Kováčová, Marie Jarošová, Michal Karas, Pavel Jindra, Hana Klamová, Kateřina Machová Poláková, Olga Černá, Eduard Cmunt, Petra Bělohlávková, Pavel Žák, Edgar Faber, Tomáš Papajík, Lukáš Stejskal, Ivana Ježíšková, Barbora Weinbergerová, Tomáš Jurček, Tomáš Horňák, Daniela Žáčková, Šárka Ransdorfová, Milena Holzerová, Tomáš Pavlík
Journal: American Journal of Hematology (2025)

The influence of t(v;22) sole, major route ACAs all (+8, n = 14; +Ph, n = 10; +19, n = 1), and -Y sole on progression-free survival. Survival curves are compared with those of patients with the standard t(9;22) translocation. Other ACAs or complex karyotypes did not influence survival. Today, the prognosis for CML patients is excellent, but some still do not respond well to therapy, progress, or die from the disease (suppl. refs. 1–4). Even in the era of tyrosine kinase inhibitors (TKIs), prognostic markers that can identify high-risk patients are still needed. Shortly after the discovery of translocation between chromosomes 9 and 22, the hallmark of CML, it became apparent that this was not the only chromosomal abnormality. In 1976, Mitelman et al. described additional nonrandom chromosomal abnormalities (ACAs) in blast phase CML, and the three most common aberrations were named "major route" (suppl. ref. 5). In the last few years, several papers analyzing larger groups of TKI–treated patients and examining the prognostic significance of ACAs have been published ([1-5], suppl. refs. 6–13). These papers show that chromosomal abnormalities do indeed play an important role. However, there are differences in the findings across reports. One explanation may be that some studies also included nonchronic phase (CP) patients or patients who developed chromosomal abnormalities during treatment, or that these studies predominantly relied on either a single-center database of patients and/or a population of patients enrolled in clinical trials. Nevertheless, there is a scarcity of data regarding the frequency and significance of these ACAs in a real-world setting. Moreover, more recently, the importance of real-world data has been emphasized, along with the fact that trial populations may not necessarily match real-world populations in an oncological setting. To expand upon existing knowledge norms in this field, we analyzed data from 1085 newly diagnosed, TKI–treated CML patients from the nationwide Czech database and examined the frequency and clinical impact of different ACAs. The patients' data were collected from the INFINITY database, comprising all TKI therapy-suitable CML patients from the Czech Republic. Treating physicians adhere to the valid international CML management recommendations. In this analysis, patients with newly diagnosed CP CML who started imatinib or nilotinib treatment between 2005 and 2019 were included. Their data were collected up to November 2023. The full dataset can be shared upon reasonable request. The study was conducted in accordance with all applicable regulatory requirements. The protocol was approved by the institutional review board and independent ethics committee. All patients provided written informed consent. Definitions of the key endpoints in this analysis followed the European LeukemiaNet recommendations [6]. Patients who intentionally stopped their treatment were censored at the time they stopped. Detailed methods are described in the Supporting Information. After obtaining the preliminary data, it was apparent that, in some patients, there could be two or more different chromosomal abnormalities, complicating classification and statistical analysis. Therefore, to analyze the significance of different cytogenetic findings, the following classification system was employed: t(v;22) sole, t(v;22) all, ACAs sole, ACAs all, major route ACAs sole, major route ACAs all, other ACAs sole, other ACAs all, -Y sole, -Y all, and complex karyotypes (Ph chromosome + at least two other chromosomal abnormalities). As the reference group, and to eliminate any bias, we selected patients with the standard t(9;22) translocation only. Moreover, we also analyzed the cytogenetic findings classified according to several published systems, summarized in Table S1. This analysis included 1085 evaluable CP CML patients, of whom 935 were initially treated with imatinib and 150 with nilotinib. The original dataset included 1315 patients, but 230 had to be eventually excluded from further analysis. The main reason was missing or unevaluable cytogenetic data at diagnosis (n = 187). Of these 1085 patients, 939 had a standard t(9;22) translocation (86.5%), 44 patients had a sole t(v;22) variant translocation (4%), and 102 patients had ACAs (9.5%). In the ACAs group, the -Y finding was also included. Basic patient characteristics are presented in Table S2. There were no significant differences between these patient subgroups, except for some minor, albeit statistically significant, differences in hemoglobin and hematocrit levels, as well as in the length of follow-up. Surprisingly, there were more deaths in the sole t(v;22) subgroup: 36.4% versus 20.4% versus 24.5% in the t(v;22), standard t(9;22), and ACA subgroups, respectively. Table S3 shows the detailed frequencies of our cytogenetic findings. In this Table, the ACAs category comprises all ACAs, including the major route ACAs, except for -Y. The other ACAs category includes ACAs, except for major route ACAs and -Y. The most prevalent findings were ACAs (n = 87), followed by t(v;22) (n = 52), and -Y (n = 20). In some patients, combinations of different cytogenetic finding categories were observed. Twenty-three patients had major route ACAs; except for one patient with an additional chromosome 19, the other patients had only +8 (n = 14) or + Ph (n = 10). Moreover, we classified our findings according to the different published classification systems to show the frequency of already-described findings in real-life settings. These data are shown in Table S1. From this Table, it is apparent that some abnormalities are very rare or not seen at all in our series of newly diagnosed real-life patients: i(17q), n = 0; +17, n = 0; +19, n = 1; +21, n = 1; monosomy 7/7q-, n = 2; 3q26.2, n = 0; and 11q23, n = 0. In the multivariate Cox regression model for OS (overall survival), analyzing age, cytogenetic findings, ELTS risk score, and several blood parameters, the following factors were significant at the level of < 0.05: age ≥ 60 years (HR 4.2, 95% CI: 3.1–5.6), higher ELTS score (HR 1.9, 95% CI: 1.4–2.6), the presence of t(v;22) (HR 2.8, 95% CI: 1.7–4.7) or major route ACAs (HR 2.5, 95% CI: 1.3–4.8), and lower hemoglobin (HR 1.4, 95% CI: 1.0–1.9). Data for PFS (progression-free survival) are similar and provided in Supporting Information. The key results regarding the different cytogenetic findings and their correlation with OS, PFS, DSS (disease-specific survival), and ATFS (alternative treatment-free survival) are summarized in Table 1 and Figure S1. The major route ACAs significantly and negatively correlated with all four studied parameters. The variant translocation also negatively impacted the prognosis. -Y was negatively correlated with PFS and ATFS. Other ACAs (i.e., ACAs except for major route ACAs and -Y), as well as the complex karyotype, did not show a significant correlation with the outcome parameters. In this Table, the other published classification systems and their impact on prognosis are also summarized. To the best of our knowledge, this is the largest study examining the prognostic significance of ACAs in CML at diagnosis in a real-life setting, and the most comprehensive comparative analysis of published ACA classification systems. Moreover, we believe that this study has several unique features distinguishing it from other reports. First, we have been able to gather the data of CML patients in the TKI era in one country with long-term follow-up. In general, there is now significant data showing that, in an oncology setting, real-life and study populations may not be identical. The second important feature of this study is that we considered only cytogenetic findings at CML diagnosis, and in patients diagnosed in CP. This contrasts with some other studies, which included patients not in CP or with clonal evolution (suppl. refs. 6–13). The third aspect is censoring patients at the time they intentionally stopped treatment for treatment-free remission. Generally, about half of these patients eventually relapse. Moreover, these patients are at very low risk with good, deep, and long-lasting responses. The fourth important aspect of this study is the statistical analysis; for the control group, we strictly included only those patients with the standard t(9;22) translocation. In 2011, Fabarius et al. [3] drew attention to the major route ACAs in CP, newly diagnosed CML patients. However, one later report did not confirm these results, while another did [1, 2]. Based on our findings, we believe that this group of cytogenetic abnormalities does indeed have a significantly negative prognostic impact. Other lesions that correlated significantly with some prognostic parameters in this study were -Y and variant translocation. Recent findings suggest that chromosome Y is important in many processes beyond determining sex, and the -Y in blood cells could become a predictive biomarker for male carcinogenesis. There are some experimental data showing that CML cells with t(v;22) may not necessarily resemble those with t(9;22) and could have enhanced MAPK pathway deregulation (suppl. ref. 14). In conclusion, major route ACAs confer a negative impact on OS, PFS, DSS, and ATFS. The variant translocation also has a significant negative impact on patient prognosis, according to our data. The loss of chromosome Y negatively correlated with PFS and ATFS and should be interpreted with caution. As the majority of patients have been treated with imatinib, we cannot exclude that other TKIs might mitigate some of the negative prognostic factors. On the contrary, complex karyotypes or other ACAs not mentioned above do not seem to significantly influence prognosis. We also showed that, in fact, only two major route aberrations prevail, and other allegedly negative prognostic aberrations are extremely rare or were not found in newly diagnosed CP CML patients. Conceptualized and designed the study, analyzed and interpreted the data, and wrote the article: Jiří Mayer. Acquired, verified, and interpreted the study data and participated in writing the final manuscript: Petra Čičátková. Verified and interpreted the cytogenetic data: Marie Jarošová. Conducted statistical analyses: Lenka Kováčová and Tomáš Pavlík. Acquired study data: Michal Karas, Pavel Jindra, Hana Klamová, Kateřina Machová Poláková, Olga Černá, Eduard Cmunt, Petra Bělohlávková, Pavel Žák, Edgar Faber, Tomáš Papajík, Lukáš Stejskal, Ivana Ježíšková, Barbora Weinbergerová, Tomáš Jurček, Tomáš Horňák, Daniela Žáčková, Šárka Ransdorfová, and Milena Holzerová. All authors had access to and verified the data, vouch for the completeness and accuracy of the data and adherence to the protocol, agreed to the content of the manuscript and submission, had access to primary clinical trial data, critically revised the manuscript, and approved the final version. This work was supported by the National Institute for Cancer Research Project (Programme EXCELES, ID Project No. LX22NPO5102), funded by the European Union—Next Generation EU, and the Czech Leukemia Study Group for Life (CELL). We would also like to thank all the patients who agreed to their data use for this analysis, and to all who cared for these patients. The study was conducted in accordance with all applicable regulatory requirements. The protocol was approved by the institutional review board and independent ethics committee of the University Hospital Brno, Czech Republic. All patients provided written informed consent. Jiří Mayer received research support from Novartis, Bristol Myers Squibb, and AbbVie, and serves as a consultant for Ascentage; Petra Čičátková and Daniela Žáčková received research support from Novartis, Bristol Myers Squibb, and Incyte; Barbora Weinbergerová received research support from AbbVie; all outside the submitted work. The other authors declare no conflicts of interest. The full dataset can be shared upon reasonable request. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.