Significance of Marker Chromosome on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for AML
Authors: Fuse Kyoko , Masuko Masayoshi , Mizuno Shohei , Harada Kaito , Uchida Naoyuki , Doki Noriko , Fukuda Takahiro , Tanaka Masatsugu , Ozawa Yukiyasu , Ikegame Kazuhiro , Eto Tetsuya , Kanda Yoshinobu , Ichinohe Tatsuo , Atsuta Yoshiko , Yanada Masamitsu 
Published: February 2021

[Background]
A marker chromosome (MAR) is a structurally abnormal chromosome that cannot be unambiguously identified or characterized by conventional chromosome analysis. MAR is considered to reflect genomic instability and is observed in 5% of acute myeloid leukemia (AML) patients. Although AML with MAR (AML/MAR+) was previously reported as refractory to chemotherapy, MAR is currently not considered associated with any specific cytogenetic risk category. Furthermore, the influence of MAR on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is unclear. Thus, to understand the characteristics of AML/MAR+ and the influence on prognosis in patients with AML, we reviewed national survey data from Japan.
[Patients and Methods]
This retrospective study included 14,099 adult patients with AML evaluable for cytogenetic risk who received their first allo-HSCT between January 1986 and December 2017. All data were sourced from the registry of the Japanese Society for Hematopoietic Cell Transplantation. The median age at allo-HSCT was 48 y (range, 16-85 y). The median follow-up period was 1.4 y (range, 0-30 y). The definition of chromosomal abnormalities adhered to the International System for Human Cytogenetic Nomenclature guidelines; chromosomal gains and structural abnormalities had to be detected in at least two metaphases, and chromosomal losses in at least three metaphases to be acknowledged as clonal. Three or more chromosomal abnormalities were defined as "complex karyotype" (CK). Cytogenetic risk was classified as favorable (n = 2,246), intermediate (n = 9,236), or poor (n = 2,617) in accordance with the criteria provided by the National Comprehensive Cancer Network Guidelines (Version 1, 2016). We defined 1st/2nd/3rd remission (n = 8,039) as "remission" and underlying disease or primary induction failure (n = 5,960) as "non-remission". Some patients (n = 100) lacked disease stage data of pre-transplantation. For MAR evaluation, clinical phenotypes were compared, and overall survival (OS) and cumulated incidence of relapse (CIR) were calculated. These variables were validated using multivariate analysis.
[Results]
MAR was detected in 668 (4.6%) of the 14,099 patients. The median age of patients with AML/MAR+ was 55 y (range, 16-77 y), and so these patients were older than AML/MAR- patients (n = 13,431; age, 48 y; range, 16-85 y; P &lt; 0.001). AML/MAR+ included more secondary AML than AML/MAR- (10.9% vs. 6.5%, P &lt; 0.001). The frequency of MAR in poor-risk AML patients (n = 580, 22.2%) was significantly higher than in favorable- (n = 13, 0.6%) and intermediate-risk (n = 75, 0.8%) AML patients (P &lt; 0.001). When the analysis was limited to poor-risk AML patients with CK (CK+AML, n = 1,368), the frequency of MAR was 42.1% (n = 576). Most cases of AML/MAR+ (n = 580, 86.8%) were categorized as poor-risk cases (vs. AML/MAR-, n = 2,037, 15.2%; P &lt; 0.001). Moreover, almost all cases of poor-risk MAR (n = 576/580, 99.3%) reflected adjuncts of CK.
Since AML/MAR+ has usually been considered poor-risk AML, especially CK+AML, we performed an evaluation focusing on these patients. First, among poor-risk AML patients, MAR was an independent risk factor of OS (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.20-1.56; P &lt; 0.001) and CIR (HR, 1.41; 95% CI, 1.15-1.72; P &lt; 0.001), based on the multivariable analysis adjusting for age, time of transplantation, performance status, disease stage, graft source, conditioning regimen, type of AML, and with/without CK. Next, in CK+AML, the 2-y-OS of CK+AML/MAR+ patients (n = 576) was 20.0% and thereby worse than that of CK+AML/ MAR- patients (n = 792, 33.2%; P &lt; 0.001). The 2-y-CIR of CK+AML/MAR+ patients was 61.4% (vs. 48.2% in CK+AML/MAR- patients, P &lt; 0.001). Furthermore, CK+AML/MAR+ patients who underwent transplant even in remission (n = 160) showed worse 2-y-OS (39.2%) and CIR (55.8%), than CK+AML/MAR- patients (n = 286, 54.5% [P = 0.004] and 37.8% [P=0.0011], respectively). In multivariable analysis adjusted for other prognosis factors, MAR was an independent risk factor of OS in CK+AML patients (HR, 1.40; 95% CI, 1.23-1.61; P &lt; 0.001) and for CIR (HR, 1.44; 95% CI, 1.17-1.77; P &lt; 0.001).
[Conclusion]
Cases of MAR almost exclusively reflected adjuncts of CK. MAR can be used to further stratify AML with CK after allo-HSCT.

Disclosures
Uchida: Sumitomo Dainippon Pharma: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka: Honoraria; Chugai Pharma: Honoraria; Novartis Pharma KK: Honoraria. Ozawa:Novartis Co., Ltd.: Honoraria. Kanda:Shionogi: Research Funding; Meiji Seika Kaisha: Honoraria; Sanofi: Honoraria, Research Funding; Mundipharma: Honoraria; Mochida Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Daiichi Sankyo: Honoraria; Shire: Honoraria; Alexion Pharmaceuticals: Honoraria; Takeda Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Novartis: Honoraria; Eisai: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Celgene: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Astellas Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria. Ichinohe:Chugai Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Company, Limited: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene Corporation: Honoraria; Repertoire Genesis: Research Funding; FUJIFILM Wako Pure Chemical Corporation: Research Funding; Takara Bio Inc.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Research Funding.