Outcomes of acute myeloid leukemia with KMT2A (MLL) rearrangement: a multicenter study of TROPHY group

Abstract

Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2A-r) is associated with poor prognosis, but the benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for KMT2A-r AML is unclear. We reviewed adult AML patients treated within the TROPHY group and identified 292 cases of KMT2A-r AML, 254 (87.0%) of whom achieved first complete remission (CR1) and 192 (75.6%) of CR1 patients underwent allo-HSCT. We show that allo-HSCT is an independent favorable prognostic factor in CR1 patients for both overall survival (OS) (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.45-0.69, P < 0.001) and cumulative incidence of relapse (CIR) (HR = 0.01, 95% CI: 0.005-0.04, P < 0.001). Among allo-HSCT recipients, survival outcomes were comparable between patients with KMT2A::MLLT3 and those with other 11q23/KMT2A rearrangements (3-year OS: 74.3% vs. 77.5%, P = 0.97; 3-year event-free survival [EFS]: 55.2% vs. 62.2%, P = 0.34; 3-year CIR: 24.4% vs. 20.8%, P = 0.32). Both multiparameter flow cytometry-based measurable residual disease (MFC-MRD) and KMT2A-r MRD determined by quantitative PCR prior to allo-HSCT were associated with worse transplant outcomes. Multivariable analysis identified detectable KMT2A-r MRD at allo-HSCT as a significant risk factor for reduced EFS (HR = 2.46, 95% CI: 1.32-4.60, P = 0.005). These findings confirm the survival benefit of allo-HSCT in adult patients with KMT2A-r AML and underscore the prognostic value of KMT2A-r MRD prior to transplantation.

Fig. 1. Flow diagram of patient enrollment.

Allo-HSCT, allogeneic hematopoietic stem cell transplantation. CR1, first complete remission.

Fig. 2. Impact of transplantation group vs. chemotherapy group on clinical outcomes in KMT2A-r AML after CR1.

The OS (A) and CIR (B) of patients who underwent allo-HSCT at CR1 compared to those who received chemotherapy only. The OS (C) and CIR (D) of patients with KMT2A::MLLT3 who underwent allo-HSCT at CR1 compared to those who received chemotherapy only. The transplantation group included patients who underwent allo-HSCT in CR1. The chemotherapy group included patients who received chemotherapy only in CR1. OS overall survival, CIR cumulative incidence of relapse, Allo-HSCT allogeneic hematopoietic stem cell transplantation, AML acute myeloid leukemia, CR1 first complete remission. Note: The 6th month after diagnosis was chosen as the landmark time. The curve does not show the censored points; the censored data are shown at the bottom along with the risk table.

Fig. 3. Multivariable analysis of clinical outcomes.

Data are provided for CR1 patients (n = 254) (A) and patients who underwent allo-HSCT in CR1 (n = 192) (B). HR hazard ratio, CI confidence interval, OS overall survival, EFS event-free survival, CIR cumulative incidence of relapse, Allo-HSCT allogeneic hematopoietic stem cell transplantation, CR1 first complete remission, Wt wildtype, WBC white blood cell, TPG translocation partner gene, MRD measurable residual disease, MFC-MRD multiparameter flow cytometry-based MRD. Note: KMT2A-r MRD cases were evaluated with specific KMT2A fusion genes. Due to the small sample size of patients with MLLT1, this mutation was combined with the “Other” group for analysis. P-values were obtained by multivariable Cox regression for OS and EFS, or by the competing risk model for CIR unless otherwise specified. Allo-HSCT was included as a time-dependent covariate in the analysis.

Fig. 4. Impact of pre-transplant MRD on clinical outcomes.

The OS of patients with positive and negative MFC-MRD before transplantation (A), the landmark analysis assessing OS within 1 year and between 1 year and 3 years after diagnosis (B), as well as the EFS (C) and CIR (D). The OS (E), landmark analysis assessing OS (F), EFS (G), and CIR (H) of patients with positive and negative KMT2A-r MRD before transplantation. KMT2A-r MRD cases were evaluated with specific KMT2A fusion genes. OS overall survival, EFS event-free survival, CIR cumulative incidence of relapse, MRD measurable residual disease, MFC-MRD flow cytometry-based MRD. Note: The curve does not show the censored points; the censored data are shown at the bottom along with the risk table.