Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia

SIMPLE SUMMARY: In order to determine the impact of KMT2A rearrangements (KMT2A-r) on the clinical characteristics and treatment outcome of pediatric acute myeloid leukemia (AML) patients, we analyzed a German population-based AML cohort of 967 patients, diagnosed between 2004 and 2019, from which 241 harbored KMT2A-r. KMT2A-r is associated with a higher disease burden and younger age at diagnosis, as well as morphologic subtype of AML M5. The 5-year overall survival rate of patients with KMT2A-r was comparable to those of patients without KMT2A-r. When analyzing AML blasts with KMT2A-r for the presence of additional genetic aberrations using different methods, e.g., classical cytogenetics, next-generation sequencing and multiplex PCR, we found the frequency of KRAS mutations increased, whereas FLT3-ITDs decreased compared to patients without KMT2A-r. Finally, we demonstrated that a correlation between CSPG4 expression and KMT2A-r exists in pediatric AML blasts; however, CSPG4 expression was not specific for blasts with KMT2A-r. ABSTRACT: KMT2A rearrangements (KMT2A-r) are among the most common structural aberrations in pediatric acute myeloid leukemia (AML) and are very important for the risk group stratification of patients. Here, we report the outcome of 967 pediatric AML patients with a known KMT2A-r status. The large cohort was characterized by morphology, multicolor flow cytometry, classical cytogenetics and mutation analysis via panel sequencing. In total, the blasts of 241 patients (24.9%) showed KMT2A-r. KMT2A-r is associated with FAB M5, a high white blood cell count and younger age at diagnosis. When subgroups were combined, KMT2A-r had no impact on event-free survival (EFS) and overall survival (OS); however, various subgroups showed a different prognosis, ranging from a <50% OS for KMT2A/AFDN (n = 11) to a 100% chance of survival for patients harboring the rare translocation KMT2A/SEPTIN9 (n = 3, follow up of 3.7 to 9.6 years). A positive correlation of KMT2A-r with KRAS mutations (p < 0.001) existed, albeit without any prognostic impact. In addition, FLT3-ITDs were detected less frequently in AML with KMT2A-r (p < 0.001). Furthermore, KMT2A-r were mutually exclusive, with mutations in NPM1 (p = 0.002), KIT (p = 0.036), WT1 (p < 0.001) and CEBPA (p = 0.006), and translocations NUP98/NSD1 (p = 0.009), RUNX1/RUNX1T1 (p = 0.003) and CBFB/MYH11 (p = 0.006). In the 346 patients tested for CSPG4 expression, a correlation between CSPG4 expression and KMT2A-r was confirmed. However, CSPG4 expression also occurred in patients without KMT2A-r and had no significant prognostic impact on EFS and OS.