In China, where matched sibling or unrelated donors are often unavailable, haploidentical donor hematopoietic stem cell transplantation (HID HSCT) plays a crucial role in treating acute myeloid leukemia (AML). However, relapse after transplant remains a major clinical challenge. Lysine (K)-specific methyltransferase 2A partial tandem duplication (KMT2A-PTD), detected in approximately 5–10% of AML cases, has been linked to poorer outcomes. While its post-transplant predictive value is established, the role of pre-transplant KMT2A-PTD levels in predicting relapse after HID HSCT has not been clearly defined. This investigation in Blood Science assessed whether pre-transplant levels of KMT2A-PTD could serve as an early biomarker for relapse risk in AML patients undergoing HID HSCT.Study Design and Methods
This single-center retrospective study analyzed 64 AML patients with KMT2A-PTD positivity at diagnosis who underwent HID HSCT between April 2016 and December 2020. Based on their KMT2A-PTD levels before transplantation, patients were divided into three groups: <0.1%, 0.1%–<1%, and ≥1%. Real-time quantitative PCR was used to monitor KMT2A-PTD, and flow cytometry was employed to assess measurable residual disease (MRD). Clinical endpoints included relapse, non-relapse mortality (NRM), leukemia-free survival (LFS), and overall survival (OS). Preemptive therapies such as interferon-α and donor lymphocyte infusions were administered post-transplant based on MRD dynamics.
Molecular Trends and Risk Dynamics
Patients with pre-transplant KMT2A-PTD ≥1% exhibited delayed MRD clearance and a slower decrease in KMT2A-PTD after HID HSCT. At three months post-transplant, only 54.5% of this group reached MRD negativity, compared to nearly 90% in patients with <0.1%. Furthermore, those with elevated pre-transplant levels were more likely to revert to molecular positivity and relapse after achieving initial remission.
Results
Among the 64 patients, the rate of MRD negativity at 1 month post-HSCT was 92.3% in the <0.1% group, 92.9% in the 0.1–<1% group, and 72.7% in the ≥1% group. At 3 months, these rates declined to 89.7%, 92.9%, and 54.5%, respectively (P = .018). Patients with KMT2A-PTD ≥1% not only cleared MRD more slowly but were also significantly more likely to revert to KMT2A-PTD positivity after initially becoming negative. In those who achieved MRD negativity, relapse occurred in 50% of patients with KMT2A-PTD ≥1%, compared to just 8.2% among those with <1% (P = .002). Additionally, pre-transplant KMT2A-PTD ≥1% was significantly correlated with concurrent MFC MRD positivity (P = .038). No statistical differences were noted in NRM, LFS, or OS between groups, but patients with higher pre-transplant KMT2A-PTD faced a clearly elevated risk of relapse.
Key Findings
The 2-year cumulative incidence of relapse was significantly higher in patients with KMT2A-PTD ≥1% before transplant (36.4%) compared to those with <1% (7.5%, P = .010). Multivariable analysis confirmed pre-transplant KMT2A-PTD ≥1% as an independent predictor of relapse (HR: 4.90; 95% CI: 1.22–19.59; P = .025). Rates of NRM, LFS, and OS did not differ significantly between groups. Interestingly, the relapse rate following preemptive intervention was the same (25%) in both high and low KMT2A-PTD cohorts, suggesting these strategies may help mitigate risk even in high-burden patients.
Conclusion
This study demonstrates that pre-transplant KMT2A-PTD levels ≥1% are a strong predictor of post-HID HSCT relapse in AML. The data suggest that molecular burden at the time of transplant significantly impacts long-term outcomes, and that MRD-guided preemptive intervention may help reduce relapse risk in high-risk patients. These findings support the integration of KMT2A-PTD assessment into pre-HSCT risk stratification protocols and warrant further validation in prospective multicenter studies.
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