Allogeneic Transplant Strategies Facilitating Donor Chimerism Might Improve Outcomes in Multihit TP53-Mutated AML/MDS

Poor outcomes following allogeneic hematopoietic cell transplant (HCT) in TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients are strongly correlated with multihit TP53 mutations, complex karyotypes, or high variant allele frequencies (VAF). Optimal HCT strategies have not yet been established for these patients. The aim of this study is to evaluate transplant outcomes of AML/MDS patients with multihit TP53 mutations, focusing on responses to various conditioning regimens and achievement of full donor chimerism (FDC) after HCT. Adults with AML or MDS who underwent next-generation sequencing (NGS)-based mutation analysis using a myeloid panel at diagnosis were evaluated. Patients without TP53 mutations were excluded. TP53 allele status was defined according to the ICC guidelines for AML and MDS. FDC was defined as > 95% donor cells tested in whole blood (WB) and T-cells by STR, qPCR, or NGS. Stringent FDC (sFDC) was > 99% donor cells, tested in WB and T-cells chimerism by qPCR or NGS. Thirty patients (14 AML, 16 MDS; median age 62) were analyzed (Table 1). Twelve AML and 4 MDS patients were in CR at HCT. All had multihit TP53 mutations, and all but 2 had complex karyotypes. The median VAF at diagnosis was 44.4%. All patients underwent peripheral blood stem cell transplantation, with 23 from unrelated donors and 17 receiving post-transplant cyclophosphamide. Patients were divided into two groups based on conditioning regimens: a “lower-intensity” group (FluBu2 or FluCy with or without 2 Gy TBI; n = 13) and a “higher-intensity” group (FluMel, FluBu4, or FluCy with 4 Gy TBI; n = 17). Median donor chimerism was lower with the low-intensity group at day 30 and 60 in WB (98.0% vs. 99.8%, p=0.057; 96.2% vs 99.9%, p=0.034) and T-cells (73.0% vs. 98.9%, p=0.095; 77.0% vs. 99.7%, p=0.022). Among all patients, the 2-year relapse, non-relapse mortality and overall survival (OS) were 65.4%, 26.4%, and 21.3%. The lower-intensity group had significantly inferior OS than the higher-intensity group (2y-OS: 7.7% in the lower-intensity and 39.3% in the-higher intensity group, p=0.04, Figure 1A). In a univariate analysis, failure to achieve FDC was associated with a higher overall mortality (WB: HR 2.67, p=0.10; T-cells: HR 4.05, p=0.01, Figure 1B), and a similar trend was observed in patients who did not achieve sFDC (WB: HR 2.46, p=0.09; T-cells: HR 2.19, p=0.16) (Table 2). Achieving FDC after HCT, especially in T-cells, may be associated with improved HCT outcomes in multihit TP53-mutated AML/MDS. Our findings support certain conditioning regimens, including 4 days of busulfan, melphalan, or 4 Gy TBI, facilitate donor chimerism conversion, potentially enhancing graft-versus-leukemia effects to reduce relapse risk. However, additional research is needed to validate our findings given the limited number of cases analyzed.