Comparison of the WHO and ICC Classifications of Cytogenetic Abnormalities in Childhood Acute Myeloid Leukemia
Authors: Sandahl Kristian Juul , Juul-Dam Kristian , Herlin Morten Krogh , Abrahamsson Jonas , Arad-Cohen Nira , Cheuk Daniel , De Moerloose Barbara , Fernandez Navarro Jose Maria , Fogelstrand Linda , Jahnukainen Kirsi , Kaspers Gertjan J.L. , Kovalova Zhanna , Munthe-Kaas Monica Cheng , Norén-Nyström Ulrika , Palle Josefine , Pasauliene Ramune , Pronk Cornelis Jan , Saks Kadri , Kjeldsen Eigil , Hasle Henrik 
Published: December 2024

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, &lt;1%) and AML with MECOM rearrangements (n = 1, &lt;1%).

Categories consistently included in WHO, AML with defining genetic abnormalities (p = 0.002) and ICC, recurrent genetic abnormalities (p &lt; 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, &lt;1%). Comparably, the distinct cytogenetic classifiers present in this cohort for ICC, AML MDSk were add(5q) (n = 1, &lt;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 &lt; 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.