Prognostic Implications of KMT2A Rearrangements and Partial Tandem Duplications in AML: Outcomes and the Role of Allogeneic Hematopoietic Cell Transplantation
Authors: Chen Li , Zhu Yongmei , Zhao Lingling , Li Jianfeng , An Ran , Liu Zhiyin , Xu Xiaoqian , Zhang Sujiang 
Published: December 2024

Background

KMT2A rearrangements (KMT2Ar) in leukemia can involve fusion with other genes or partial tandem duplication (KMT2A-PTD). A small number of patients may present with both KMT2Ar and KMT2A-PTD simultaneously. The impact of these three genetic alterations on the prognosis of acute myeloid leukemia (AML) patients remains unclear.

Aims

Investigate and compare the molecular characteristics and survival of AML patients with KMT2Ar and/or KMT2A-PTD, and to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) in these patients.

Methods

A retrospective analysis of newly diagnosed AML patients with KMT2Ar and/or KMT2A-PTD at our center from February 2019 to May 2023. This study focused on their clinical characteristics, molecular profiles, treatment protocols, and outcomes. All participants provided informed consent.

Results

The cohort consisted of 125 patients, including 111 de novo and 14 secondary AML (sAML) cases. There were 56 males and 69 females, with a median age of 51 years (range: 14-74). Among the sAML patients, 11 had a history of solid tumors and 3 of hematologic malignancies. Notably, 12 (86%) patients of sAML were female.

Forty-five patients had KMT2Ar, 64 had KMT2A-PTD, and 14 had both. Common fusion partners for KMT2Ar included MLLT3 (n=16), AFDN (n=14), ELL (n=14), MLLT10 (n=8), and other less common types (ARHGEF12, CREBBP, MLLT1, MLLT6, MYH11, SEPTIN6, USO1 each in 1 case). Among patients with both KMT2Ar and KMT2A-PTD, the partner genes were MLLT3 (n=2), AFDN (n=5), ELL (n=6), and SEPTIN6 (n=1). Different genetic mutations often accompanied KMT2Ar and KMT2A-PTD. The most common co-occurring mutations in KMT2Ar were KRAS (17%), PTPN11 (17%), NRAS (14%), STAG2 (12%), ASXL1 (12%), and GATA2 (12%). For KMT2A-PTD, frequent mutations included DNMT3A (39%), FLT3-ITD (34%), RUNX1 (26%), IDH2 (26%), WT1 (19%), U2AF1 (14%), and IDH1 (14%). Patients with both KMT2Ar and KMT2A-PTD had genetic profiles more closely resembling those of the KMT2Ar group, with common mutations in KRAS (21%), PTPN11 (14%), and ASXL1 (14%).

Out of 120 patients who received treatment, 93 underwent intensive chemotherapy and 27 received reduced-intensity therapy. The evaluable complete remission (CR) rate was 54% following the initial induction, increasing to 69% after the second induction therapy. There was no significant difference in CR rates between the two treatment intensities (p=0.231). Additionally, CR rates did not differ among the KMT2Ar, KMT2A-PTD, and KMT2Ar with KMT2A-PTD groups.

After a median follow-up of 16.9 months (range: 0.2-54.5 months), the estimated 3-year overall survival (OS) and event-free survival (EFS) rates were 51% and 42%, respectively. The median OS was 38.6 months (range: 21.1-56.1 months) and the median EFS was 23.7 months (range: 9.5-37.9 months). No significant differences in OS (p=0.469) and EFS (p=0.795) were observed between patients with de novo AML and sAML. The median EFS for KMT2Ar, KMT2A-PTD, and both KMT2Ar and KMT2A-PTD groups were 31.8, 18.8, and 17.6 months, respectively (p=0.854). However, within the KMT2Ar group, the median EFS for patients with MLLT3 and ELL rearrangements were not reached. For those with AFDN, it was 7.3 months, and for other KMT2Ar, it was 3.9 months. For KMT2A-PTD group, the median EFS was 17.6 months (p=0.016).

Patients were then divided into three risk groups: intermediate-risk (MLLT3 and ELL rearrangements), high-risk (KMT2A-PTD), and very high-risk (other KMT2Ar). The 3-year EFS rates were 71%, 40%, and 25% (p=0.003). The 3-year OS rates were 78%, 51%, and 35% (p=0.044). Common co-occurring mutations in KMT2Ar and KMT2A-PTD did not significantly impact OS and EFS.

Sixty-eight patients underwent allo-HCT, significantly improving survival. The 3-year OS rate was 75% with HCT vs. 23% without (p&lt;0.001), and EFS was 66% vs. 12% (p&lt;0.001). Subgroup analysis revealed HCT significantly improved OS and EFS for high-risk KMT2Ar (p&lt;0.001, p=0.036) and KMT2A-PTD (both p&lt;0.001), but not for MLLT3 and ELL rearrangements (p=0.460, p=0.574).

Conclusion

Although KMT2A::ELL is classified as adverse prognosis, our data show similar outcomes between KMT2A::ELL and KMT2A::MLLT3. KMT2A-PTD prognosis falls between ELL and MLLT3 and very high-risk KMT2Ar. Allo-HCT is recommended for KMT2A-PTD upon remission.