Over the past decade, advancements in understanding the molecular basis of acute myelogenous leukemia (AML) have led to improved treatments and outcomes. Now, researchers are focusing on eliminating 'leftover' disease, known as measurable residual disease (MRD), to further enhance remission rates and prevent relapse.
Eradicating Measurable Residual Disease
Jacqueline Garcia, MD, a medical oncologist at Dana-Farber, is leading efforts to eradicate MRD, which refers to the small number of leukemia cells that remain after treatment and are undetectable by standard bone marrow biopsies. These cells can drive recurrence, and researchers are using deep DNA sequencing to identify them.
Phase 1 Trial: Venetoclax to Target MRD
Garcia is leading a phase 1 clinical trial (NCT03613532) for high-risk patients with myelodysplastic syndrome and AML. These patients often receive reduced-intensity conditioning treatment before stem cell transplants. The trial evaluates the addition of venetoclax to the conditioning chemotherapy and a hypomethylating agent plus venetoclax as post-transplant maintenance therapy in patients with high-risk disease features. The goal is to reduce or prevent the expansion of MRD, thereby reducing the risk of relapse.
"Venetoclax doesn’t interfere with the transplant process from what our studies show and allows us to squash the chance of leftover disease from growing into a relapse," Garcia says. Venetoclax inhibits the BCL-2 protein, inducing cell death in tumor cells and has shown efficacy in certain blood cancers.
Randomized Clinical Trial Development
Early data from the phase 1 trial has been promising, leading to the development of a randomized clinical trial through the National Cancer Institute myeloMatch program. This trial will assess MRD conversion and critical outcomes like event-free survival.
Collaborative Research to Detect and Treat MRD
Garcia is also part of a collaborative Break Through Cancer grant, along with other Dana-Farber investigators, focusing on novel ways to detect and treat MRD in AML patients. The team aims to study existing and new AML treatments, collecting blood and bone marrow samples to better detect MRD and understand its meaning within different disease-associated genetic mutations.
"AML is a complex and heterogeneous disease, so one person’s AML is definitely different from the next," Garcia notes. The team plans to dissect the biology of MRD to identify factors influencing its behavior and pathways leading to relapse.
Tailored MRD Testing
The researchers aim to develop different types of MRD tests for various patient subsets to avoid overtreatment or undertreatment and intervene only when necessary.
