Liquid biopsy technologies, particularly circulating tumor DNA, or ctDNA, are changing how clinicians monitor hematologic malignancies. In this interview, Dr. Oksana Fabri explains how ctDNA provides a dynamic, systemwide view of disease burden that complements bone marrow biopsies and imaging while reducing the need for invasive procedures. Serial ctDNA measurements can detect molecular relapse months before clinical progression and are associated with progression-free and overall survival.
The discussion also highlights the close connection between ctDNA and minimal residual disease, or MRD. Traditional MRD methods measure residual malignant cells directly, often through bone marrow sampling. ctDNA offers a less invasive, complementary approach by detecting tumor-derived DNA in plasma, allowing clinicians to capture disease heterogeneity and track clonal evolution over time.
From a clinical development perspective, ctDNA is increasingly used to refine endpoints and response assessment in hematologic cancer trials. Dr. Fabri discusses its growing role in biomarker-driven study designs, adaptive trials and the evaluation of durable MRD-negative responses, including in therapies such as CAR T-cell treatments and bispecific antibodies.
Stephanie Butler:
Welcome. I am Stephanie Butler with Fierce Biotech, and I am delighted to be joined here today by Dr. Oksana Fabri, who is the Senior Medical Director, Therapeutic Area Medical Lead of Hematology and Oncology at Allucent. And before we begin, I’d love to just get a little background on you, Oksana and Allucent. So welcome.
Dr. Oksana Fabri:
Thank you, Stephanie. So my name is Oksana Fabri. I’m a physician hemato-oncologist, and I work always 17 years in the clinical and research background. I used to work at the clinic as physician, hemato-oncologist, and transplant physician. And since 2021, I work for Allucent, contract research organization and serve as a therapeutic area medical lead and provide medical oversight to studies, from early to late studies within the therapeutic area. And happy to be here.
Stephanie Butler:
Yeah, delighted to have you. I want to start by talking about liquid biopsy technologies, especially particularly ctDNA assays. They’re getting a lot of attention now in oncology research. So I’d love to hear from you, how are these approaches changing the way clinicians can monitor hematologic malignancies?
Dr. Oksana Fabri:
Thank you, Stephanie. This is actually a highly relevant and strategically important topic for the field right now. Liquid biopsy and ctDNAs assays, especially fundamentally changing how we monitor hematological malignancies. So lipid biopsy allows clinicians to quantify tumor derived DNA in plasma and other body fluids. And by that, it provides a dynamic system-wide view of disease burden that complements bone marrow and imaging. In hematologic malignancies, serial ctDNA measurements can track clonal dynamics, detect emerging resistant mutations, and identify molecular relapse months before clinical or radiographic progression becomes evident. When we look from the patient perspective, it is also a big win since it reduces the need for repeated invasive procedures and allows for more frequent assessment. And importantly, the data are quite compelling. ctDNA has become and has shown to be highly specific for active disease, and is associated with outcomes like progression-free survival and overall survival. So it’s not just convenient, it is clinically meaningful. Overall, I see ctDNA increasingly being integrated into both clinical trials and routine practice, mainly as a complementary to alongside standard assessment rather than replacing them.
Stephanie Butler:
With its advantage to patients, and some of the things that I’m also hearing about ctDNA, we’re hearing it discussed alongside minimal residual disease or MRDs. So how are these concepts connected in hematologic cancers?
Dr. Oksana Fabri:
So ctDNA and minimal residual disease or measurable residual disease are very closely related. So they are actually different ways of looking at the same underlying concept, which is residual disease below the level of conventional detection. Traditionally, MRD has been assessed using multiparameter flow cytometry or highly sensitive molecular assays on bone marrow or blood samples. These methods actually look at residual malignant cells directly. ctDNA, on the other hand, is essentially a liquid biopsy approach to MRD. Instead of measuring cells, the tumor derived DNA fragments circulating in the plasma are detected, typically by using highly sensitive sequencing or digital PCR methods. One of the key advantages is that ctDNA can provide a more systemic view of the disease. It’s not limited to a single biopsy site or single time point, so it can better capture heterogeneity of the disease across different compartment. So conceptually, I think that ctDNA is expanding the MRD toolkit. As I mentioned, it doesn’t replace traditional approaches, but it adds a complementary, less invasive, and potentially more comprehensive way to assess deep remission.
Stephanie Butler:
So if it doesn’t replace the traditional monitoring approaches, it’s complementary to it, but what advantages then does the ctDNA-based assays offer for detecting residual disease or early relapse?
Dr. Oksana Fabri:
Traditional methods like bone marrow biopsy, flow cytometry, molecular assays and cellular DNA and imaging, they are all informative, but invasive, episodic, and sometimes insufficiently sensitive or specific for early molecular relapse. ctDNAs assays can detect multiple somatic variants at very low directions with studies in hematology and other cancers showing sensitivity, down to 0.03% variant LL frequency for MRD detection. So as the assays mature and the data compelling, the key evidence are growing for these methods. And I would like to highlight a few of them. So first of all, it is non-invasiveness and feasibility of frequent sampling, which enables richer longitudinal kinetics. Next is earlier detection of relapse with ctDNA becoming positive several months before clinical or imaging evidence of progression in lymphomas or leukemias. With this method, we are able to monitor clonal evolution and resistant mechanism through multi-parameter profiling, mutational profiling, which is not routinely achievable and available with conventional MRD assays. And finally, it has strong prognostic value, where we know that high or persistent ctDNA correlates with inferior progression-free survival and overall survival. So together, all these features support ctDNA as sensitive real-time surrogate for residual disease and early relapse risk.
Stephanie Butler:
So it definitely has some distinctive advantages, but if we look at it from a clinical development perspective, how can ctDNA and MRD monitoring influence endpoints or response assessment in hematologic cancer trials?
Dr. Oksana Fabri:
This is a very hot topic in current research. And in clinical development, ctDNA and MRD create opportunities to refine endpoints beyond traditional radiographic comorphological criteria. One application would be incorporating ctDNA-based MRD negativity as an intermediate or surrogate endpoint, particularly in early phase clinical trials to enable earlier signal detection of biological activity and guide go, no-go decisions. So dynamic ctDNA kinetics such as early clearance, depth of reduction, and time to molecular relapse, they all can be used to risk stratify patients, adapt therapy intensity, and enrich or deescalate cohorts in the adaptive trial designs. Currently, regulatory groups and expert panels started to support ctDNA as a primary efficacy endpoint in selected phase two settings, while still recommending its use as a key secondary and exploratory endpoint in later phase trials until robust data are accumulated. So in hematological malignancies, aligning ctDNA-based MRD definitions with established MRD frameworks will be critical to harmonize response assessment and facilitate cross-trial comparisons.
Stephanie Butler:
Oh, definitely. I want to ask, what role do you see ctDNA playing in the future of biomarker-driven trials and hematologic malignancies? So we know biomarkers are a topic of hot discussion, so I’d love to hear the role that it would play in those.
Dr. Oksana Fabri:
I think ctDNA might become a central biomarker across the entire clinical trials lifecycle, especially in hematological malignancies. So at baseline, it can support molecular profiling, especially when the tissues are limited. And with that, we can help identify actionable mutations or high-risk disease, which is key for biomarker enriched and stratified trial designs. During the treatment, ctDNA really adds value through real-time monitoring. Changes in the ctDNA levels can help guide treatment decisions, for example, identifying patients who may need intensification versus those who could potentially benefit from deescalation if they achieve deep molecular responses. And post-treatment, ctDNA-based MRD opens the door to earlier intervention. So detecting molecular relapse before clinical progression could allow for more proactive treatment strategies and potentially long-term outcomes. So overall, as the technology matures and becomes more standardized, I see and think that ctDNA becoming included across eligibility, stratification, response assessment, and surveillance, essentially becoming a co-biomarker in hematology trials, similar to what we have already seen in solid tumors.
Stephanie Butler:
Yeah, the potential is really kind of exciting when you explain it like that. I do want to look ahead and ask how could ctDNA and MRD monitoring help researchers better understand the durability of MRD-negative responses from therapies, such as CAR-T and bispecific antibodies?
Dr. Oksana Fabri:
Yeah, this is a very hot topic of professional debates in professional community since this therapy is advancing very rapidly. So for therapies like CAR T-cell and bispecific antibodies, achieving MRD measurable residual disease negativity is the key goal, but the real question is how durable those responses are. And this is where ctDNA may be particularly valuable. So with serial monitoring, we can go beyond a single MRD-negative time point and really assess the depth and stability of response over time.
For example, early ctDNA clearance after treatment has been shown to correlate with better response rates and longer progression-free survival. On the other hand, persistent or reemerging ctDNA can be an early sign of resistance or impending relapse. What is important that ctDNA also allows us to look at the biology, not just the presence or absence of the disease. By profiling mutation all the time, we can start to identify emerging resistant clones and better understand mechanisms of treatment escape.
When we integrate ctDNA with other pharmacodynamic markers, which are specific for these kind of therapies like CAR T-cell expansion or immune activation, we can begin to define what truly durable MRD negativity looks like versus more transient responses. So overall, I would say that the ctDNA has potential to refine how we assess the durability and ultimately inform decisions around treatment duration, monitoring strategy, and even retreatment approaches.
Stephanie Butler:
With such potential here as you’re discussing, what role do CROs play in helping sponsors integrate these emerging biomarkers like ctDNA into their clinical trials?
Dr. Oksana Fabri:
So CRO, I think, plays a critical role in translating biomarkers like ctDNA from concept into something that is actually usable in global clinical trials. First, on the strategy side, we work closely with sponsor to define how ctDNA fits into the trial, selecting the right assays, setting up sampling schedules, and aligning biomarker objectives with endpoints and overall statistical plan. Second, we build the operational infrastructure, and that includes standardizing sample collection, processing, and logistic across sites, as well as managing central labs and quality systems to ensure data consistency. We also help navigate the regulatory landscape. As expectations from agencies like FDA, EMA evolve, we ensure that assays are properly validated, and that the data are generated and reported in a way that supports regulatory and health technology assessment discussions. And finally, we enable integrated data analysis, so bringing together ctDNA with clinical and imaging data to generate meaningful insights. So overall, I think CROs are really the bridge between the scientific innovation and execution, helping de-risk biomarker integration and make it actionable in clinical development.
Stephanie Butler:
It’s so important to be able to take these technological innovations and put them into actual practice so we can actually get to helping patients in the end. But we’ve covered a lot today, so we really want to thank you, Dr. Fabri and Allucent for such an engaging discussion. I’m really looking forward to see how this develops down the road, so definitely keep me posted and thank you to everyone for listening.
Dr. Oksana Fabri:
Thank you very much, and thank you for inviting us.
