AFFILIATIONS
1 Aarhus University Hospital, Aarhus, Denmark, Aarhus University, Aarhus, Denmark
2 Aarhus University Hospital, Aarhus, Denmark, Aarhus University, Aarhus, Denmark
3 Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
4 University Hospital Essen, Essen, Germany
5 Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel
6 Princess Maxima Center, Utrecht, Netherlands
7 Hong Kong Children's Hospital and The University of Hong Kong, Hong Kong, China, Hong Kong Pediatric Hematology and Oncology Study Group, Hong Kong, China
8 Seattle Children's Hospital, University of Washington,, Seattle, WA, United States
9 Jagiellonian University Medical College, Krakow, Poland
10 Hospital Nacional Prof. Dr. Alejandro Posadas, Buenos Aires, Argentina, Pediatric Acute Myeloid Leukemia Group (GATLA), Buenos Aires, Argentina
11 Semmelweis University, Budapest, Hungary
12 St. Luke's International Hospital, Tokyo, Japan
13 Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom
14 New Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
15 Tallinn Children's Hospital, Tallinn, Estonia
16 Princess Maxima Center, Utrecht, Netherlands
17 Ljubljana University Medical Centre, Ljubljana, Slovenia
18 Aglaia Kyriakou Children's Hospital, ELPIDA Children's Oncology Hospital, Athens, Greece
19 Goethe University Frankfurt, Frankfurt am Main, Germany
20 Children's Clinical University Hospital, Riga, Latvia, Rigas Stradinsh University, Riga, Latvia
21 Ghent University Hospital, Ghent, Belgium
22 Oslo University Hospital, Rikshospitalet, Oslo, Norway
23 Hospital Universitario y Politécnico La Fe, Valencia, Spain
24 Umeå University, Umeå, Sweden
25 Children's Hospital, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
26 Dana-Farber/Boston Children’s Cancer and Blood Disorders Center; Harvard Medical School, Boston, MA, United States
27 Lund University, Lund, Sweden, Skåne University Hospital, Lund, Sweden
28 Great Ormond Street Hospital for Children NHS Foundation Trust, London, London, United Kingdom
29 University Children's Hospital Zurich, Zurich, Switzerland
30 Motol and Homolka University Hospital, Prague, Czech Republic, Second Faculty of Medicine, Charles University, Prague, Czech Republic
31 University of Debrecen, Debrecen, Hungary
32 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, United States, Seattle Children's Hospital, University of Washington,, Seattle, WA, United States
33 Yokohama City University Hospital, Yokohama, Japan
34 Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
35 Aarhus University Hospital, Aarhus, Denmark, Aarhus University, Aarhus, Denmark
36 Aarhus University Hospital, Aarhus, Denmark, Aarhus University, Aarhus, Denmark
37 Aarhus University Hospital, Aarhus, Denmark
ABSTRACT
Pediatric acute myeloid leukemia (AML) comprises distinct cytogenetic and molecular subgroups with variable prognosis. AML with myelodysplasia-related cytogenetic abnormalities (MRC) have been associated with inferior outcomes. Given the cytogenetic heterogeneity, it remains unclear whether this adverse prognosis is intrinsic to the entire group or driven by MRC-defining karyotypic features such as monosomy 7 or deletion of 7q (-7/del(7q)) or trisomy 8 (+8). Recognizing that the rarity of AML-MRC in children has hampered comprehensive characterization, we investigated MRC in a large cohort of pediatric AML patients within the International-Berlin-Frankfurt-Münster (I-BFM) AML study group. Children diagnosed with de novo AML-MRC according to the 2022 International Consensus Classification between 2000-2022 were identified through the Nordic Society of Pediatric Hematology and Oncology (NOPHO) AML registry, the I-BFM AML study group, and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. AML patients without MRC were identified within the NOPHO AML registry and used for comparison. Standard time-to-event analyses including Cox regression were used to assess predictors of 5-year overall and event-free survival (OS/EFS). Multivariate analysis included age, white blood cell count, protocol era and FLT3-ITD. The association between stem cell transplantation (SCT) in first complete remission (CR1) and outcome was evaluated by including SCT as a time-dependent covariate in Cox regression. A total of 450 AML-MRC patients were identified along with 930 patients without MRC. More patients with MRC had resistant disease (15% vs. 6%, p<0.01) and more often received SCT (39% vs. 18%, p<0.01) in CR1. The most abundant AML-MRC-defining abnormalities were +8 (n=157, 35%) followed by -7/del(7q) (-7: n=79, del(7q): n=44, total: n=123, 27%), abnormalities of 5q (n=44, 10%), 17p (n=38, 8%) and 12p (n=28, 6%). Complex karyotype (CK), defined as ≥ 3 unrelated cytogenetic abnormalities, was present in 298/450 AML-MRC patients (66%) of whom 189 (63%) also presented with another MRC-defining abnormality. Among MRC patients, FLT3-ITD was present in 51/427 (12%), most frequently in combination with +8 (36/51, 61%). Patients with MRC had a lower OS and EFS (58%, 95% confidence interval [CI]:53-63 vs. 76%, CI:73-79, p < 0.01 and 42%, CI:37-47 vs. 59%, CI:55-62, p<0.01). Within the AML-MRC cohort, none of the defining subsets showed a distinct inferior prognosis in terms of OS; CK: 60%, CI:54-65; 5q abnormalities: 51%, CI:31-68, -7/del(7q): 63%, CI:53-72; +8: 55%, CI:46-63; 12p abnormalities: 46%, CI:26-64; 17p abnormalities: 43%, CI:25-60. Comparable estimates were observed for EFS as well except for patients with 12p abnormalities who had a lower EFS (24%, CI:10-41 vs. 43%, CI:38-48, p=0.04). There were no differences in outcomes between patients with -7 or del(7q) (OS:63%, CI:50-74 vs. 64%, CI:45-76, p=0.9 and EFS:47%, CI:35-58 vs. 36%, CI: 21-51, p=0.6). FLT3-ITD had no adverse effect on OS and EFS among AML-MRC patients (53%, CI: 37-67 vs. 61%, CI:55-66, p=0.5 and 36%, CI:23-45 vs. 44%, CI:38-49, p=0.2) with the exception of patients with +8/FLT3-ITD who showed lower EFS compared to patients with +8/FLT3-wildtype (26%, CI:12-41 vs. 45%, CI:36-54, p=0.05). CK had a favorable impact on OS in patients with -7 (n=35; 76%, CI:55-89) compared to -7 without CK (n=42, 53%, CI:6-67, p=0.03). The favorable effect of CK was not observed in any other MRC-defining abnormality. In multivariate analysis, MRC was associated with lower OS and EFS (adjusted hazard ratio [HR]:2.1, CI:1.7-2.5, p<0.01 and HR:1.8, CI:1.5-2.1, p<0.01). Within the MRC cohort, abnormalities of 12p remained independently associated with an inferior EFS (HR:1.7, CI:1.1-2.8, p =0.02), while -7 in combination with CK remained associated with superior OS in multivariable analysis (HR:0.4, CI:0.2–1.0, p =0.04). Among AML-MRC patients, SCT in CR1 was not associated with improved OS (HR:0.9, CI:0.6-1.3, p=0.5). This study provides the most comprehensive characterization of pediatric AML-MRC. AML-MRC was associated with inferior outcomes, which was not overcome by SCT as consolidation therapy. Our findings underscore the need of molecular characterization to identify disease pathways amenable for targeted therapies and improve outcomes for children with this high-risk subtype of AML.