# Impact of Fusion Partners and Transplantation Benefit in Intensively Treated KMT2A-Rearranged Acute Myeloid Leukemia

## TL;DR

This study shows that KMT2A-rearranged AML patients with specific fusion partners, like KMT2A::ELL, have better survival, and that stem cell transplantation benefits older patients more than younger ones.

## Contribution

The study identifies age-dependent HSCT benefits and KMT2A::ELL as a favorable subtype in KMT2A-rearranged AML.

## Key findings

- Patients with KMT2A::ELL fusion had significantly better 3-year overall survival (59.8%) compared to other subtypes (39.3%).
- Hematopoietic stem cell transplantation (HSCT) significantly improved survival in patients over 20 years old but not in those aged 20 or younger.
- Age and HSCT in first complete remission were independently associated with better overall and event-free survival.

## Abstract

Acute myeloid leukemia with KMT2A rearrangements is challenging, characterized by diverse clinical outcomes. Given the varied clinical outcomes across different KMT2A fusion subtypes, the specific benefit of hematopoietic stem cell transplantation (HSCT) for each subgroup remains under-investigated, which is critical for making precise treatment decisions in the era of emerging targeted therapies. In this study, we analyzed 181 KMT2A-rearranged patients to determine how different fusion partners affect clinical outcomes. We found that patients with KMT2A::ELL had better outcomes compared to others. Crucially, our research revealed that the benefit of HSCT is highly dependent on patient age. While HSCT significantly improved survival for patients over the age of 20, it did not provide a statistically significant survival advantage for patients aged 20 or younger. We suggest that treatment decisions, especially regarding HSCT, should be personalized based on both the specific genetic characteristics and the age of the patient to optimize survival chances.

Background: KMT2A rearrangements are a frequent genetic abnormality associated with Acute myeloid leukemia (AML), historically linked to varied prognoses and outcomes. The prognosis for patients with this rearrangement remains controversial, necessitating further research to stratify risk and guide treatment. Methods: In this retrospective study, a total of 3468 adolescent and adult AML patients were screened, and 181 patients harboring KMT2A rearrangements were analyzed. We used FISH, RT-PCR, and next-generation sequencing, including transcriptome and targeted panels, for diagnosis and mutation profiling. All patients received intensive chemotherapy. We evaluated overall survival and event-free survival using Kaplan–Meier and Cox regression models, with HSCT analyzed as a time-dependent variable. Results: The incidence of KMT2A-rearranged AML in our newly diagnosed cohort was 5.9%. Among the 181 patients included in the final analysis, 89 (49.2%) were male and 92 (50.8%) were female, with a median age of 33 years (range: 13–65). The distribution of fusion partners included KMT2A::MLLT3 (n = 39), KMT2A::AFDN (n = 27), KMT2A::MLLT10 (n = 25), KMT2A::ELL (n = 24), and others (n = 12). Seventy-four patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). The median follow-up for survivors was 17.53 months (range 1.47–112.57), and the 3-year overall survival (OS) and event-free survival (EFS) for the entire cohort were 42.0% and 32.1%, respectively. Patients with KMT2A::ELL exhibited superior OS compared to other subtypes (3-year OS [ELL vs. non-ELL]: 59.8% vs. 39.3%, p = 0.023). Concomitant mutations did not significantly impact the prognosis of KMT2A-rearranged AML patients. In multivariate analysis, age and HSCT in CR1 were independently associated with OS and EFS (OS: HR = 1.022, p = 0.026 [age]; HR = 0.238, p < 0.001 [HSCT]; EFS: HR = 1.027, p = 0.002 [age]; HR = 0.155, p < 0.001 [HSCT]). Patients aged over 20 years were more likely to benefit from HSCT than those aged 20 years or younger (p < 0.001 [age > 20], p = 0.780 [age ≤ 20]). Conclusions: Our study revealed the heterogeneous outcomes of KMT2A-rearranged AML patients and clarified the impact of HSCT across different age groups.