Role of Chromosomal Microarray and RNA Fusion Analysis in Detecting KMT2A Partial Tandem Duplication with High Mortality in Myeloid Neoplasms: Retrospective Study

KMT2A partial tandem duplication (KMT2A-PTD) is a recurrent, high-risk alteration in myeloid neoplasms, yet no gold standard exists for its detection due to complex genomic architecture. We conducted a retrospective study of 97 specimens from 17 patients with KMT2A-PTD-positive myeloid neoplasms (11 AML, 4 MDS, 2 MPN) to compare chromosomal microarray analysis (CMA) and RNA fusion testing. Overall concordance was 73.3% ({kappa} = 0.467), with RNA fusion identifying more cryptic KMT2A-PTDs (p = 0.035), while CMA detected non-canonical KMT2A-PTDs and, additionally, secondary genomic abnormalities (e.g., trisomy 8 and CN-LOH of diverse genes). KMT2A-PTD cases exhibited high clonal complexity and distinct mutational profiles, including mutations of DNMT3A, TET2, ASXL1, RUNX1, FLT3, and others. Higher KMT2A-PTD transcript expression (split reads and SR/C ratio) correlated with DNMT3A, RUNX1, and FLT3 mutations, and RUNX1T1 copy number gain (p < 0.05), and was reduced in CN-LOH cases. RNA fusion consistently identified breakpoints at exon 10[-&gt;]2 or exon 11[-&gt;]2, affecting key oncogenic domains (CXXC, PHD finger, and bromodomain). Six-month overall survival was 41.2%, with HSCT significantly improving outcomes (68.6% vs. 0% at 17 months, p = 0.028), non-transplanted patients showing shorter median PFS ([~]6 months), and FLT3-mutated patients experiencing 100% mortality (p = 0.0456). In conclusion, CMA and RNA fusion analyses offer complementary diagnostic value in KMT2A-PTD-positive myeloid neoplasms. Such integrated genomic testing improves detection and refines risk stratification. Given the poor prognosis associated with KMT2A-PTD, especially in patients with co-occurring high-risk mutations, our findings support early consideration of HSCT in such patients.