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322 Comparison of the WHO and ICC Classifications of Cytogenetic Abnormalities in Childhood Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Treatments and Outcomes in AML in Specific Age Groups, and in Blastic Plasmacytoid Dendritic Cell Neoplasms
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Epidemiology, Clinical Research, Pediatric, Diseases, Myeloid Malignancies, Study Population, Human
Saturday, December 7, 2024: 4:45 PM

Kristian Juul Sandahl, MD1*, Kristian Juul-Dam, MD2*, Morten Krogh Herlin3*, Jonas Abrahamsson, MD, PhD, Professor4*, Nira Arad-Cohen5*, Daniel Cheuk6*, Barbara De Moerloose, MD, PhD7*, Jose Maria Fernandez Navarro8*, Linda Fogelstrand, MD9, Kirsi Jahnukainen10*, Gertjan J.L. Kaspers, MD, PhD11, Zhanna Kovalova12*, Monica Cheng Munthe-Kaas13*, Ulrika Norén-Nyström, MD, PhD14*, Josefine Palle15*, Ramune Pasauliene16*, Cornelis Jan Pronk, MD, PhD17*, Kadri Saks18*, Eigil Kjeldsen, Professor19* and Henrik Hasle2

1Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Aarhus N, Denmark
2Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
3Department of Genetics, Aarhus University Hospital, Aarhus, Denmark
4Department of Pediatrics, Institute for Clinical Sciences, University of Gothenburg, Gothenburg, Sweden
5Department of Pediatric Hemato-Oncology, Rambam Health Care Campus, Haifa, Israel
6Department of Pediatrics and Adolescent Medicine, Hong Kong Children's Hospital and Hong Kong Pediatric Hematology and Oncology Study Group (HKPHOSG), Hong Kong, China
7Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
8Department of Pediatric Hemato-Oncology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
9Region Vastra Gotaland, Sahlgrenska University Hospital, Gothenburg, Sweden
10New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
11VU University Medical Center, Utrecht, Netherlands
12Department of Paediatric Oncology/Haematology, Children's Clinical University Hospital, Riga, Latvia
13Department of Pediatrics, Oncology and Hematology, Oslo University Hospital, Oslo, Norway
14Department of Clinical Sciences, Pediatrics, Umeå University Hospital, Umeå, Sweden
15Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
16Center of Oncology and Hematology, BMT Unit, Vilnius University Children's Hospital, Vilnius, Lithuania
17Childhood Cancer Center, Skåne University Hospital, Lund, Sweden
18Department of Hematology Oncology, Tallinn Children´s Hospital, Tallinn, Estonia
19Department of Hematology, Aarhus University Hospital, Aarhus, Denmark

Acute myeloid leukemia (AML) is caused by genetic abnormalities in myeloid progenitors. These abnormalities are categorized in the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and The International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias. The WHO and ICC classifications are mainly derived from adult AML cohorts, but distinct patterns of cytogenetic abnormalities exist between children and adults with AML.

We present a comparison of the WHO and ICC cytogenetic classifiers in a large cohort of children with AML.

Children with AML were included from The Nordic Society for Pediatric and Hematology and Oncology (NOPHO) database between 2004 - 2021. NOPHO spans the Nordic and Baltic countries. Since 2012 NOPHO-DB-SHIP also includes Hong Kong, the Netherlands, Belgium, Spain, and Israel. Inclusion criteria were de novo non-M3-AML aged 0 - 18 years at diagnosis. Children with myeloid leukemia of Down syndrome, juvenile myelomonocytic leukemia, therapy-related AML and AML secondary to inherited bone marrow failure or predisposition syndromes were excluded. Children were treated as per the NOPHO AML 2004 or the NOPHO-DBH AML 2012 protocol. Classification was based on cytogenetics, i.e., cryptic or molecular variants were included in WHO, AML defined by differentiation or ICC, AML Not Otherwise specified (NOS). KMT2A-rearrangements (KMT2A-r) other than MLLT3::KMT2A were included in ICC, AML with other KMT2A-r. The Kaplan-Meier method was used to estimate overall survival (OS) with 95% confidence intervals (CI).

We identified 1,080 children of whom 1,021 (95%) children had available diagnostic cytogenetics. More children (n = 694, 68%) were treated as per the NOPHO-DBH AML 2012 protocol.

The three largest entities in WHO, AML with defining genetic abnormalities were AML with KMT2A-r (n = 259, 25%), AML with RUNX1::RUNX1T1 fusion (n = 142, 14%), and AML with CBFB::MYH11 fusion (n = 90, 9%). The three largest entities in ICC, AML with recurrent genetic abnormalities were AML with RUNX1::RUNX1T1 fusion (n = 142, 14%), AML with other KMT2A-r (n = 138, 14%), and AML with MLLT3::KMT2A fusion (n = 121, 12%). Rare entities in WHO, AML with defining genetic abnormalities and ICC, AML with recurrent genetic abnormalities were DEK::NUP214 fusion (n = 10, 1%), AML with BCR::ABL fusion (n = 2, <1%) and AML with MECOM rearrangements (n = 1, <1%).

Categories consistently included in WHO, AML with defining genetic abnormalities (p = 0.002) and ICC, recurrent genetic abnormalities (p < 0.001) had significant differences in OS. AML with CBFB::MYH11 fusion had the highest 5-year OS (88%; CI: 82 - 95%) followed by AML with RUNX1::RUNX1T1 fusion (85%; CI 79 - 91%). WHO, AML with KMT2A-r had a 5-year OS of 75% (CI: 70 - 81%). We observed no difference in 5-year OS comparing ICC, AML with MLLT3::KMT2A (OS: 74%; CI: 66 - 83%, p = 0.8) to ICC, AML with other KMT2A-r (OS: 0.76%; CI: 69 - 84%).

WHO, AML defined by differentiation included 367 (36%) children and ICC, AML NOS included 339 (33%) children. WHO, AML, Myelodysplasia-related (MR) included fewer children (n = 119, 12%) than ICC, AML with myelodysplasia-related cytogenetic abnormalities (MDSk) (n = 147, 14%). The only distinct cytogenetic classifier present in this cohort for WHO, AML MR was del(11q) (n = 1, <1%). Comparably, the distinct cytogenetic classifiers present in this cohort for ICC, AML MDSk were add(5q) (n = 1, <1%) and +8 (n = 28, 3%). Children with +8 only included in ICC, AML MDSk were significantly older at diagnosis (median: 13 years, range: 1 - 18 years, p < 0.001) but their 5-year OS was not significantly different (OS: 65%; CI: 47 – 90, p = 0.4) compared with other children included in AML MDSk (median: 4 years, range: 0 - 18 years, OS: 61%; CI: 51 - 72%). WHO, AML MR (OS: 61%; CI: 52 - 71%, p = 0.001) and ICC, AML MDSk (OS: 62%; CI: 54 - 71%, p = 0.002) had a significantly lower 5-year OS than WHO, AML defined by differentiation (OS: 74%; CI: 69 - 79%) and ICC, AML NOS (OS: 75%; CI: 70 - 80%), respectively.

Using cytogenetic classifiers, the WHO and ICC had similar prognostic capabilities in childhood AML and were able to identify children with a poor prognosis despite differences in defining myelodysplasia-related cytogenetic abnormalities.

Cytogenetic classification leaves one third of children with AML as WHO, defined by differentiation or ICC, NOS underlining the need to characterize molecular variants driving childhood AML.

Disclosures: Kaspers: Syndax: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH