Jeff Sharman, MD, on Advances in Non-Hodgkin Lymphoma Treatment

For patients with lymphoma, the therapeutic landscape looks markedly different than it did just a few years ago, with an expanding arsenal of novel treatment approaches. In recognition of World Lymphoma Awareness Day, Targeted Oncology^TM sat down with Jeff Sharman, MD, to discuss the evolving treatment landscape for non-Hodgkin lymphoma (NHL). As advances in immunotherapy, targeted therapies, and cellular therapy continue to expand treatment options, the field is also grappling with how best to incorporate these approaches into clinical practice and address remaining unmet needs.

In this interview, Sharman, chair, Lymphoma Research Executive Committees, SCRI at Willamette Valley Cancer Institute & Research Center, discussed key developments in NHL treatment, ongoing challenges for patients across lymphoma subtypes, and areas of research that could shape the future of lymphoma care.

Targeted Oncology: What have been some of the key advancements in NHL treatment over the past few years?

Jeff Sharman, MD: NHL [treatment] has undergone a significant transformation within the last few years. There are a handful of technologies that have been brought to bear on the disease that have really been reshaping our treatment algorithms. The first and most prominent might be the use of bispecific antibodies. These are antibodies that differ from the natural type of antibodies that function like the letter Y, and at the end of each arm have grabbers for their target. What's unique is that those grabbers are different, so they can be used to bridge different targets, and in this case, we're bringing together T cells and their B-cell targets. In doing so, it activates the T cells to kill the B cells. These have been approved for patients with relapsed disease and are moving earlier in the treatment algorithm, and we're hoping to see fairly soon, maybe within the next 12 to 24 months, whether or not these could even move to the frontline setting, based upon a handful of trials that are going on. There are a handful of these agents out there, and each of them are quite active, and we're still trying to figure out the best place to use these.

Another technology that's been impactful in the field is chimeric antigen receptor [CAR] T-cell cell therapy. In the aggressive lymphomas, what we call diffuse large B-cell lymphoma, CAR T has been present for a while, but we're expanding the accessibility to them, so they're [increasingly] becoming available. But in various other different types of lymphoma, approvals have been forthcoming in the last 12 to 24 months, and so more and more patients can benefit from these therapies.

We've also seen targeted therapies [like Bruton tyrosine kinase (BTK)] inhibitors and BCL2 inhibitors playing more and more of a role, each having a role in certain subtypes of lymphoma. Those agents have offered patients impressive disease control with oftentimes very well tolerated oral therapies. The most recent one was the approval of sonrotoclax [Beqalzi] in mantle cell lymphoma, and we look forward to seeing additional clinical trials with that agent. Finally, antibody-drug conjugates have played an expanding role in aggressive lymphoma, with polatuzumab vedotin [Polivy] and other agents in clinical development. We're, of course, hopeful that both [polatuzumab vedotin] and other investigational agents will find an expanded role in the management of these diseases.

What unmet needs still exist in the patient population?

We've made significant progress in many of the different histologies, but I think we have to acknowledge there's still room for improvement. If you take the most common lymphoma, diffuse large B-cell lymphoma, we probably cure between two-thirds to three-quarters of patients with therapy, but that still leaves room for patients who aren't cured, and we need to push those numbers higher, perhaps by earlier utilization of CAR T in high-risk groups, or novel strategies such as using measurable residual disease [MRD] at the end of therapy to stratify for consolidation therapy. These are investigations under approach.

With lower grade histologies—follicular lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, mantle cell lymphoma—we're making progress, but that progress still has room for more progress. We can do better, and I think it is exciting to see several of the agents in clinical development [for which] we will hopefully find places where we can utilize these therapies more broadly.

Looking ahead, what developments are you personally excited about as the treatment landscape evolves?

In the next few years, the expanded role of bispecifics, I think, is going to be important. We could potentially see these agents moving into the frontline setting, bringing modern immunotherapy to the frontline setting, which I think would be a great step forward for patients. I think that in the CAR T-cell space, we're seeing not only the success of autologous CAR T-cell therapies, but we're now exploring the role of allogeneic CAR T cells. These don't require individual patient manufacturing; they can be made in advance and ready for a patient when needed, and we're looking at that in the consolidation setting for large B-cell lymphoma. I think using MRD testing to identify those patients at highest risk of relapse is another advance moving forward. There's a handful of approaches that could bear further progress in the field of lymphoma.

FAQs

What are bispecific antibodies in lymphoma treatment? Bispecific antibodies are engineered antibodies with 2 different target-binding arms. In lymphoma, they bridge T cells and B cells, activating the T cells to kill the cancerous B cells. They are approved for relapsed disease and are being studied for earlier use, including in the frontline setting.

What is CAR T-cell therapy used for in lymphoma? CAR T-cell therapy is used most extensively in diffuse large B-cell lymphoma and has recently gained approvals across additional lymphoma subtypes, expanding access for more patients.

What is the cure rate for diffuse large B-cell lymphoma? According to Jeff Sharman, MD, roughly two-thirds to three-quarters of patients with diffuse large B-cell lymphoma are cured with current therapy.

What is allogeneic CAR T-cell therapy? Allogeneic, or "off-the-shelf," CAR T-cell therapy is manufactured in advance from donor cells rather than a patient's own cells, so it can be ready for use without the delay of individual patient manufacturing. It is being studied in the consolidation setting for large B-cell lymphoma.