MRD Response-adapted Allo-HSCT for Adverse-risk AML

Overview

This TROPHY-AML01 regimen aims to identify the effectiveness and safety of MRD response-adapted allo-HSCT for adverse-risk acute myeloid leukemia in an open-label, randomized, controlled trial.

1.1 Relapse is the most important cause of transplant failure Acute myeloid leukemia is one the most important hematologic malignancies for adults. According to the criteria of European LeukemiaNet (ELN) 2022, approximately 40%-50% of AML patients were categorized into adverse-risk group. The clinical outcomes of these patients receiving chemotherapy alone is poor and the 4-year probability of leukemia-free survival (LFS) after therapy is nearly 10%. Thus, allogeneic hematologic stem cell transplantation (allo-HSCT) is considered as the critical consolidation in adverse-risk AML patients, and many AML patients could achieve long-term LFS after allo-HSCT. However, nearly one third of the adverse-risk AML patients would experience relapse after allo-HSCT, and the outcomes of patients with post-transplant are very poor and relapse is also the most important cause of mortality after allo-HSCT. Thus, how to prevent post-transplant relapse is important to further improve the survival of patients with adverse-risk AML. 1.2 Measurable residual disease (MRD) can predict the relapse of AML after treatment. The detection of MRD is one of the most important methods for defining the depth of remission. Using current sensitive techniques, the presence of 1 residual leukemia cell in 10 000-1 000 000 cells can be detected in patients with morphological complete remission (CR). The most commonly used method for MRD assessment involves (1) the determination of leukemia-associated immunophenotypic patterns (LAIPs) using multiparameter flow cytometry (MFC) and (2) the quantitative polymerase chain reaction (qPCR)-based evaluation of expression levels of leukemia-related genes, such as recurrent genetic abnormalities and other mutation types. 1.3 Pre-transplant MRD can predict the relapse of AML after allo-HSCT. MFC is one of the most common methods for MRD monitoring and is the most important method for MRD monitoring for those without leukemia-specific molecular markers. In the systemic review of Buckley et al., pre-transplant MRD was associated with worse LFS (hazard ratio \[HR\] = 2.76 \[1.90-4.00\]), overall survival (OS, HR = 2.36 \[1.73-3.22\]), and cumulative incidence of relapse (HR = 3.65 \[2.53-5.27\]). 1.4 The prognostic value of pre-transplant MRD positivity is controversial in adverse-risk AML. Pre-transplant MRD positivity could predict relapse after allo-HSCT, however, its prognostic value may be more significantly in patients with favorite- and intermediate-risk group. Some authors suggested that pre-transplant MFC MRD was less important in predicting relapse than variables reflecting the biology of the disease (e.g., cytogenetics, molecular marker, or chemotherapy refractory). Receiving repeated consolidation to achieve pre-transplant MRD negativity may not decrease the risk of relapse and improve survival, and patients may experience relapse during consolidation chemotherapy and may suffer additional therapeutic toxicities which may increase the risk of non-relapse mortality after allo-HSCT.

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