A Q&A with Mark Roschewski, MD, Lymphoma Specialist, Memorial Sloan Kettering Cancer Center.
Mark Roschewski, MD, is a lymphoma specialist at Memorial Sloan Kettering Cancer Center (MSK) who treats aggressive B-cell lymphomas and leads many of the institution’s clinical trials in diffuse large B-cell lymphoma. He helped develop and validate blood-based testing for circulating tumor DNA (ctDNA) while at the National Cancer Institute, research he has continued at MSK. In this conversation, he discusses two innovations he believes will define the next era of lymphoma care: targeted agents and ctDNA-based blood testing.
Q: What drives your approach to treating aggressive B-cell lymphomas?
A: Mission-based medicine is in my blood, instilled by years spent with the US military in fellowship training, residency, and active service. As an expert in treating B-cell lymphomas, my goal is always to cure as many patients as possible.
Q: How much progress have we made curing these cancers, and what still stands in the way?
A: Today we cure about 75% of patients with aggressive B-cell lymphomas. Immunotherapy, over the last decade, has helped us succeed in roughly half of the cases we previously could not cure once chemotherapy failed, and other options were exhausted. But what about the remaining 25%? How can we cure more of them?
Q: Where do you see the next wave of progress coming from?
A: I believe two innovative modalities will define the next wave in lymphoma care: targeted agents and blood-based testing.
Q: Let’s start with targeted agents. How have they changed treatment?
A: For years, trying to cure a patient who stopped responding to chemotherapy meant delivering more chemotherapy at higher doses. There was no orthogonal approach, no way to attack the disease differently. Targeted agents, pills, and medicine delivered precisely to the cancer cell, rather than to any dividing cell, changed the game. In combination with immunotherapy, targeted agents are helping us cure patients who would have run out of options a decade before. And these therapies are only going to get better.
Q: And the second modality, blood-based testing?
A: The second modality involves blood-based tests that measure disease far more precisely than imaging scans. These tests can help us make more informed treatment decisions, pivot to a new course when the current one is not working, and more definitively determine whether cancer is gone from the body. My prediction: the next era of lymphoma care will be built not on scans, but blood.
Q: You helped develop ctDNA testing. Tell us about that.
A: Blood-based testing to detect ctDNA, small fragments of DNA shed by cancer cells into the bloodstream, is an approach I helped develop and validate while at the National Cancer Institute. I have continued to build on that research here at MSK. ctDNA tests (also known as liquid biopsies) can measure disease down to one cancer cell among a million healthy ones, sometimes one in ten million. This gives us the ability to measure disease at a molecular level.
Q: How does that compare to what imaging can detect?
A: Imaging cannot approach such resolution. A one-centimeter tumor visible on a CT or PET scan represents roughly a billion cancer cells. A normal scan that shows no tumor does not rule out disease. It only means the disease has dropped below what imaging can detect.
Q: How does this change the way we think about remission?
A: This is an important distinction when we are trying to accurately define remission. Remission simply means we cannot see the cancer. Roughly 15% of patients who reach remission will relapse. We typically spend years monitoring patients in remission to confirm they are truly disease-free. This means repeating clinic visits, scans, additional testing and potentially years of uncertainty. But with blood-based tests, we can give patients a more definitive answer right at the end of therapy. If their tests come back negative, we can confidently tell them their relapse risk is almost zero: around the 1% to 2% range. That is a much better conversation to have.
Q: How might ctDNA testing change treatment decisions during a course of therapy?
A: New paradigms now being tested in clinical trials involve patients with normal imaging scans who still show evidence of a tumor from ctDNA testing. Should we treat those patients before their disease shows up on a scan? That is one question these trials seek to answer. Blood-based tests can also tell us early if a patient is not responding to their treatment, two months into a six-month regimen, for example. The next wave of research in this area will be response-adaptive studies designed to pivot patients to new treatments as needed based on real-time data, instead of maintaining them on a fixed protocol course.
Q: What studies is MSK leading in this space?
A: At MSK, we are leading studies like this in aggressive lymphoma. Some are smaller studies conducted here, because there are still a lot of clinical nuances to work out. Others are larger national and international trials, several of which we are helping design and expect to play a central role in conducting. We currently have one open study we are modifying now to focus on these blood-based tests, with a broader set of related trials slated to open by early next year. These larger trials are made possible in part by recent consolidation among diagnostic companies that can run testing at scale.
Q: What does it take to get research like this off the ground?
A: I spend a great deal of my time interacting with diagnostic companies, as well as industry partners and regulatory agencies. Launching large clinical trials requires us to build consortiums of stakeholders who share the same vision and are moving in the same direction. The phrase I often think of is, “If you want to go fast, go alone. If you want to go far, go together.” At MSK, we want to go as far as we can in advancing the care of patients with B-cell lymphomas.
Q: Why is getting the underlying biology right so important for lymphoma patients?
A: Diffuse large B-cell lymphoma, the subtype I run the most trials for, is a genuinely heterogenous disease. When considering enrollment in a trial or clinical treatment for a patient at MSK, we must first recognize the biology of lymphoma. It is not a single disease. It is at least 100 different subtypes, arguably closer to 1,000 if you want to split hairs, and each one behaves differently and responds to treatment differently. This heterogeneity is why a one-size-fits-all approach fails patients. A regimen that may cure one subtype can be the wrong choice for another, in part because every therapy carries some toxicity. Matching the right approach to the right biology determines whether the tradeoff is worth it.
Q: How does MSK approach genomic profiling?
A: Getting the biology right starts with genomic profiling. At MSK, nearly every patient diagnosed with lymphoma has their tumor sent for a large mutation panel called MSK-IMPACT. That level of molecular detail is not available everywhere. It is one of the leading-edge medical tools we use to sharpen our decisions about how to treat patients according to their specific tumor biology.
Q: How does collaboration factor into the care MSK provides?
A: Collaboration is an essential component of oncology. Success requires close collaboration among clinical and research teams within MSK, referring physicians and patients themselves. Inside MSK, collaboration runs in both directions. Lab scientists work directly with clinicians in the traditional bench-to-bedside approach that has defined translational science. But it also runs the other way: bedside observations often send clinicians back to the lab to understand why a treatment worked or why it did not.
Q: How do you work with referring physicians?
A: We work closely with referring physicians to let them know what trials we have available and discuss the reasons they might consider enrollment for a particular patient. As I have said, lymphoma is a heterogenous disease and even if a patient meets a clinical trial’s enrollment criteria, their biology might not make them the right fit. Talking through the details with referring physicians is essential to matching the right patient to the right trial. Collaboration among clinicians is also indispensable in the treatment of uncommon lymphomas, where we have fewer approved drugs and established standards. It can get tricky, especially for oncologists who see all kinds of cancers, not just lymphoma. But even lymphoma-focused physicians can find unusual presentations challenging. My team and I are happy to collaborate and consult as needed in these challenging cases.
Q: How does that approach extend to patients themselves?
A: This spirit of collaboration extends to patients as well. We do not hand patients a menu of equally weighted options for their lymphoma care. We give them our recommendations and reasoning and, if they see it differently, we talk through the issues.
Q: What’s the mission that ties all of this together?
A: At MSK, the patient is always at the center of the mission-based approach to the care my team and I provide. MSK’s mission is ending cancer for life, and I believe blood-based tests are the next wave in treatment that will get us closer to accomplishing that mission in more patients. Our clinicians will always do what is best for the patient, which is the reason we have such a strong reputation for providing expert, comprehensive care. From leadership, through our scientists and clinicians, right down to the person who first answers the phone, we all focus on the patient as an individual, getting people in to see us faster than anywhere else I have ever been, and tailoring care to their individual needs, even as those needs change over time.