Clonal Evolution and Immune Dysregulation in AML patients treated with Venetoclax and Azacitidine after Allogeneic Stem Cell Transplantation

About This Grant

Project Summary Allogeneic stem cell transplantation (allo-SCT) is the only potentially curative therapy for AML. However, relapse of AML post-transplant remains the major cause of failure and continues to be a significant challenge. Understanding the mechanism behind post-transplant relapse is crucial for developing effective prevention and treatment strategies. Studies suggest that relapse after allo-SCT is multifactorial, involving the expansion of residual leukemia, potentially with new driver mutations. Immune escape mechanisms enable leukemic cells to evade the graft-versus-leukemia effect, in addition to T cell exhaustion and dysregulation. One strategy to prevent relapse is maintenance or pre-emptive therapy with anti-leukemic agents, with a low risk of graft failure and good tolerability after allo-SCT. To address this, we have conducted multiple clinical trials and are currently running a phase II trial evaluating venetoclax (Ven) with azacitidine (AZA) posttransplant, (NCT04128501). In this trial, patients receive this combination either for maintenance or to eradicate minimal residual disease (MRD) after transplant. Additionally, we are collecting longitudinal blood and bone marrow samples from participating patients as part of this study. In this proposed study, our aims are as follows: 1) To characterize the mutational landscape at diagnosis, post-transplant, and at relapse in AML patients receiving venetoclax and azacitidine after allogeneic SCT, utilizing single cell DNA sequencing to explore relapse mechanisms 2) To define T cell evolution in AML patients receiving venetoclax and azacitidine post- transplant, and the immune mechanisms that eradicate MRD with this combination. We have unique advantages in this research. Current data on post-transplant genetics mainly derive from next generation sequencing, whole exome sequencing, or flow cytometry, all with limitations. High throughput single-cell genomic analysis enables the detection of mutation cooccurrences within individual cells and determination of the order in which mutations appear. Post-transplant milieu cannot be analyzed solely by disease-specific genetic alterations but also immune-related changes. Given the association of T cell clonal emergence and immunotherapy response, we will also analyze T cell receptor repertoires and immune profiles post-transplant. This will help determine whether a specific subgroup benefit from Ven and AZA, particularly for patients with impending relapse, such as those with MRD detection. As a summary, in this exploratory grant, we will focus on mutational landscape and T-cell clonality to assess responders to Ven and AZA in the post-transplant setting. If successful, our project will provide critical information to identify which patients are more likely to benefit from Ven and AZA for disease prevention and guide tailored post-relapse treatments based on individual disease and immune-related findings.