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. 2023 May;70(5):e30251.
doi: 10.1002/pbc.30251. Epub 2023 Feb 15.

Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group

Karen M Chisholm  1   2 , Jenny Smith  3 , Amy E Heerema-McKenney  4 , John K Choi  5 , Rhonda E Ries  3 , Betsy A Hirsch  6 , Susana C Raimondi  7 , Yi-Cheng Wang  8 , Alice Dang  8 , Todd A Alonzo  9 , Lillian Sung  10 , Richard Aplenc  11 , Alan S Gamis  12 , Soheil Meshinchi  3 , Samir B Kahwash  13
Affiliations

Pathologic, cytogenetic, and molecular features of acute myeloid leukemia with megakaryocytic differentiation: A report from the Children's Oncology Group

Karen M Chisholm et al. Pediatr Blood Cancer. 2023 May.

Abstract

Background: Acute myeloid leukemia (AML) with megakaryocytic differentiation (AMkL) is a rare subtype of AML more common in children. Recent literature has identified multiple fusions associated with this type of leukemia.

Methods: Morphology, cytogenetics, and genomic sequencing were assessed in patients from Children's Oncology Group trials AAML0531 and AAML1031 with central-pathology review confirmed non-Down syndrome AMkL. The 5-year event-free survival (EFS), overall survival (OS), and RR were evaluated in these AMkL subcategories.

Results: A total of 107 cases of AMkL (5.5%) were included. Distinct fusions were identified in the majority: RBM15::MRTFA (20%), CBFA2T3::GLIS2 (16%), NUP98 (10%), KMT2A (7%), TEC::MLLT10 (2%), MECOM (1%), and FUS::ERG (1%); many of the remaining cases were classified as AMkL with (other) myelodysplasia-related changes (MRC). Very few cases had AML-associated somatic mutations. Cases with CBFA2T3::GLIS2 were enriched in trisomy 3 (p = .015) and the RAM phenotype, with associated high CD56 expression (p < .001). Cases with NUP98 fusions were enriched in trisomy 6 (p < .001), monosomy 13/del(13q) (p < .001), trisomy 21 (p = .026), and/or complex karyotypes (p = .026). While different 5-year EFS and OS were observed in AMkL in each trial, in general, those with CBFA2T3::GLIS2 or KMT2A rearrangements had worse outcomes compared to other AMkL, while those with RBM15::MRTFA or classified as AMkl-MRC fared better. AMkL with NUP98 fusions also had poor outcomes in the AAML1031 trial.

Conclusion: Given the differences in outcomes, AMkL classification by fusions, cytogenetics, and morphology may be warranted to help in risk stratification and therapeutic options.

Keywords: CBFA2T3::GLIS2; NUP98 fusions; acute megakaryoblastic leukemia; acute myeloid leukemia; pediatric acute myeloid leukemia.

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Conflict of interest statement

CONFLICT OF INTEREST DISCLOSURE

The authors report no financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Fusions present in acute myeloid leukemia with megakaryocytic differentiation.
In this study, 61 of 102 patients with available cytogenetic data had identified fusion proteins.
Figure 2.
Figure 2.. Oncoprint illustrating fusions present in pediatric AMKL, and their co-operating cytogenetic abnormalities and mutations.
The abnormalities present in chr13 (Abn13) include del(13q), monosomy 13, trisomy 13, and chr13 translocations. Additional cytogenetic aberrations reported are copy number variations (trisomy 3, trisomy 6, monosomy 7/del7q, and monosomy5/del5q).
Figure 3.
Figure 3.. AMkL vs other AML Kaplan–Meier curves per trial.
(A) Event-free survival and (B) overall survival of all cases of AMkL (FAB M7) versus all other centrally-reviewed AML FAB subtypes from trial AAML0531. As shown, M7 cases have relatively equivalent EFS and OS compared to other FAB subgroups. (C) EFS and (D) OS of all cases of AMkL versus all other centrally reviewed AML FAB subtypes from trial AAML1031; as shown AMkL have decreased 5-year OS compared to the other FAB subgroups. In general, AMkL on AAML0531 had better outcomes than AMkL on AAML1031.
Figure 4.
Figure 4.. AMkL subgroup Kaplan–Meier curves per trial.
(A) Event-free survival and (B) overall survival of major AMkL subgroups in trial AAML0531 show statistically significant different survivals depending on the identified fusion, other myelodysplasia-related changes (MRC), or not otherwise specified (NOS). (C) Event-free survival and (D) overall survival of major AMkL subgroups in trial AAML1031 did not show statistically significant different survivals depending on the subcategory.
See this image and copyright information in PMC

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