Over the last decade, significant strides have been made in understanding the molecular underpinnings of acute myelogenous leukemia (AML) in adults, which has led to better drugs and better treatment outcomes for patients. This shifting landscape now makes it possible for cancer researchers and providers to ask, “How can we do better?”
Dana-Farber medical oncologist Jacqueline Garcia, MD, and her colleagues are among this group of trailblazers working to advance the frontiers of AML care.
“It used to be that the treatment goal in adults with AML was palliative, where we would focus on disease control because that’s really all we could do — the treatments were limited in their efficacy and others were just too toxic for most patients,” Garcia says. “Now, our expectations have really shifted, and we’re asking, ‘Can we get patients in remission? And, if so, how deep of a response can we get? Can we transplant patients who we didn’t think were candidates for transplant before?’” In AML, stem cell transplants can produce longer-lasting remissions of disease and potentially can be curative.
She is leading a handful of research efforts in AML that are aimed at eradicating “leftover” disease — known in technical terms as measurable residual disease (MRD). This refers to the small quantities of leukemia cells that are left behind after treatment and that conventional tests, such as a bone marrow biopsy, are not sensitive enough to detect by morphology (or “by eye”).
The idea is that even when AML patients may be considered generally disease-free from a microscope, there can be a small population of cancer cells left behind that drive recurrence. Researchers can identify these culprit cancer cells use deep DNA sequencing techniques, which can detect small numbers of cells by analyzing their genetic material.
For example, Garcia is leading an investigator-initiated, phase 1 clinical trial (NCT03613532) for high-risk patients with myelodysplastic syndrome and AML. These patients, who tend to be older, are generally treated with a stem-cell transplant. Because of their age, they are offered a reduced-intensity conditioning treatment, which is the chemotherapy regimen that clears the bone marrow and prepares it to receive the transplant. While the regimen is considered quite safe, about half of patients go on to relapse. In addition, older patients with AML have a higher rate of high-risk genetic mutations, which are also associated with poor outcomes.
This phase 1 trial is evaluating the addition of venetoclax to the conditioning chemotherapy that is given right before transplant or donor cell infusion, and the addition of a hypomethylating agent plus venetoclax as post-transplant maintenance therapy in patients who have high-risk disease features. The goal is to try to reduce MRD or prevent it from expanding and, therefore, reduce the risk of relapse. Venetoclax is an inhibitor of the BCL-2 protein that leads to cell death in tumor cells; it has proven particularly effective in certain blood cancers.
“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. “This clinical trial is just one way for us to try to address measurable residual disease, which is the leftover disease that you cannot see by eye.”
The initial data from this early trial has been so compelling that Garcia and her colleagues in Alliance and the BMT CTN are in the process of developing a randomized clinical trial for patients with AML through the National Cancer Institute myeloMatch program.
“Now that we’ve demonstrated tolerability and safety in our phase one trial, this randomized study will look at MRD conversion and outcomes that are critical, such as event-free survival,” said Garcia.
Garcia is also an investigator on a major, collaborative Break Through Cancer grant, together with Dana-Farber investigators Andrew Lane, MD, PhD; Benjamin Ebert, MD, PhD, president and CEO of Dana-Farber Cancer Institute; and Richard Stone, MD. The grant includes other top leukemia centers as well as a laboratory collaborator (MIT). With this grant funding, the researchers are focusing on how to detect and treat MRD in AML patients in a novel way and in a team-based approach, instead of operating in silos.
“AML is a complex and heterogeneous disease, so one person’s AML is definitely different from the next,” Garcia says. “Right now, clinicians use one clinical test to measure MRD for most cases of AML, but that doesn’t always pick up every case that’s likely to relapse. It is a quantitative and qualitative issue.”
The team plans to study existing as well as novel AML treatments, and collect both blood and bone marrow samples from patients across the participating clinical sites. The goal is not only to better detect MRD, but also to study what MRD means within the context of different disease-associated genetic mutations using multiple different tools. In addition, a dedicated research team is dissecting the biology of MRD to identify factors that influence the behavior of this important cell population and identify the pathways the lead to relapse — and those that don’t.
“We’ll likely need different types of MRD tests for different subsets of patients,” she adds. “Our ultimate goal is not to overtreat or undertreat, and to intervene only when we need to.”