How Promising Are Immunotherapy Combos in Indolent Lymphoma?

Lorenzo Falchi, MD, highlighted the most important considerations when using novel immunotherapy combination therapies for patients with indolent lymphoma.

During the Society of Hematological Oncology (SOHO) 2025 Annual Meeting, Lorenzo Falchi, MD, an oncologist and hematologist specializing in lymphoma at the Memorial Sloan Kettering Cancer Center, delivered a presentation titled “Novel Immunotherapy Combinations in Indolent Lymphoma”.

Following that presentation, Falchi spoke with CancerNetwork® on the current landscape of immunotherapy in indolent lymphomas. He discussed the importance of formulating combination therapies, the most prevalent combinations currently available, and the potential drawbacks or toxicities associated with their use.

CancerNetwork: Why was this topic on immunotherapy combinations in indolent lymphoma important to present?

This presentation had a strong rationale to occur at SOHO because the time is ripe for a serious talk about combinations, including active immunotherapies in patients with indolent, slow-growing diseases. [There] is an unmet need for novel therapies that can ensure longer durations and higher [probabilities] of responses, including deep responses, because the old dogma that we have been taught in medical school is that patients with indolent lymphoma and follicular lymphoma have a lesser chance of a response and a shorter duration of benefit with each subsequent line of therapy.

That is true for conventional standard therapies that include rituximab [Rituxan], but in the novel era of T-cell-based immunotherapies, we are witnessing a paradigm shift where patients now experience much longer durations of benefit, [with] much higher complete response [CR] rates and much deeper responses. Minimal residual disease [MRD] testing is showing that most patients who have a radiographic CR also have a clearance of their MRD. [This] indicates the power of chemotherapy-free approaches for the treatment of this prevalent lymphoma.

What were the most prominent takeaways from the presentation?

The first takeaway was that bispecific antibodies are novel therapies, but from a pharmacokinetic point of view, they are well-known because they are immunoglobulin-like molecules. They are adaptable, versatile, and easy to combine with a variety of partner chemotherapy or immunotherapy agents. It is also particularly easy to combine them because their modes of action tend to be peculiar and distinct from those of other drugs—for example, lenalidomide [Revlimid]—and also because their toxicity profiles are largely non-overlapping with those of other drugs that we combine them with.

The second takeaway is that the type of responses and efficacy that we have seen with these combinations rival what we have in our standard of care armamentarium. All the studies that have been conducted have shown that the efficacy of bispecific combinations probably compares favorably with standards of care. On that basis, several randomized control trials have been launched to test that hypothesis, both in the relapsed setting and, most recently, in the frontline setting. We have 5 separate randomized control trials internationally testing chemotherapy-free bispecific combinations against standard-of-care chemoimmunotherapy. Having done some of the early studies in this space, I have a good feeling about these trials. I am hopeful that we can not only challenge, but beat, the current standard of care, and, once and for all, get rid of cytotoxic conventional chemotherapy for these patients.

What are the most prevalent combinations?

Lymphoma therapy in general is hardly ever a one-man show. It's hardly ever a monotherapy, with the possible exception of CAR T-cell therapy. Some of the more efficacious and powerful treatments for lymphoma in general, [and in] follicular lymphoma in particular, are combinations of multiple anti-lymphoma drugs. This is also true for bispecific antibodies, and this is what I tried to outline in my presentation. For example, lenalidomide, which is an immunomodulating drug, has been a natural partner for bispecific antibodies alone or with rituximab, and the results with combined lenalidomide and bispecifics have been promising. Most patients achieve a CR.

In the study testing epcoritamab [Epkinly] with rituximab and lenalidomide, we enrolled 111 patients. This is a large international phase 2 trial where we saw that 87% of the patients achieved a CR and at 21 months of follow-up, 80% of the patients were progression-free. In addition to that, if one looks at the MRD-negative response of patients who cleared their MRD, their chance of response and progression-free survival was even higher. This data suggested that the types of responses and the depth of responses with this combination were promising.

Other combinations have been tested. One that I am particularly excited about is with what's called costimulatory bispecific antibodies—it's a bispecific-bispecific duet. The first bispecific, the primary bispecific, was glofitamab [Columvi], and the second bispecific, the adjuvant or secondary bispecific, is the costimulatory…englumafusp alfha [CD19-4-1BBL]. It's a promising drug because it attaches to the lymphoma cells, like the primary antibody, and to the T cell, delivering signal 2 to the T cell, and that boosts the T-cell activation and the ability to kill off the lymphoma cells.

That's a beautiful theoretical concept, but the question was, “Is it going to work in clinical practice?” There has been a large first-in-human phase 1 trial internationally, demonstrating that 79% of the 24 enrolled patients with follicular lymphoma had a CR, and the majority of them held that response at a relatively long follow-up of almost 36 months. We have a sense that we can top the results of single-agent bispecific antibodies in multiple ways.

There are other combinations that have been tested with standard chemotherapy. [They are] not particularly elegant but they have been effective with antibody drug conjugates with our cohort of patients with indolent lymphomas who have been enrolled in those studies, as well. We are going to be awaiting the results of those particular trials. Finally, there are some other drugs in the immunomodulatory space—for example, golcadomide [BMS-986396]—which have been combined with bispecific antibodies along similar lines to the lenalidomide combinations. The lenalidomide combinations with bispecifics, so far, have the most mature data; so much so that the biggest phase 3 randomized controlled trials are testing the lenalidomide bispecific combination against various standards of care.

What toxicities are most important to consider when choosing a treatment?

With each novel technology or treatment modality, we all come to learn [of] new toxicities. This has certainly been the case for bispecific antibodies. When CAR T-cell therapy was developed, there was a great deal of effort on the part of the whole academic research community to better understand the specific toxicities that are cytokine release syndrome [CRS] and neurotoxicity, such as [immune-effector cell-associated neurotoxicity syndrome (ICANS)] or ICANS-like syndromes that are unique to this treatment modality.

Bispecific antibodies are also associated with CRS and potential neurotoxicity; [it’s a] bit of a different profile, as these toxicities are less frequent and, generally speaking, less severe. It certainly has been a learning curve, and bispecific antibodies being more scalable than CAR T-cell therapy poses a larger question to our community oncology colleagues and other physicians who have not been familiar with immunotherapies, and now, all of a sudden, will have these drugs in their hands. There is [significant ongoing] education. We and others put together international recommendations for how to best manage CRS and neurotoxicity. There will be a learning curve for most practitioners, but eventually CRS and neurotoxicity will be mastered.

What has been an emergent toxicity that initially we have not talked about enough, but now what we are all keenly aware of—and [Dr. Laurie H. Sehn, MD, MPH], gave a wonderful presentation associated with warnings of this particular toxicity—is infectious disease complications, or infections. Most of these infections are respiratory infections, viral infections, bacterial infections, or anything [derived] from sinusitis to pneumonia. These patients are at risk of those infections, and there is not a well-established, or any agreed-upon, algorithm or guideline on how to best manage these.

Each center has its own experience. In our own experience, for example, when we start a patient on a bispecific antibody for a recurrent lymphoma, we will ensure these patients have a [Varicella-Zoster Virus (VZV)] prophylaxis with acyclovir or valacyclovir, or a [pneumocystis jirovecii Pneumonia (PJP)] prophylaxis with [trimethoprim-sulfamethoxazole] or similar drugs. We will have a low threshold to use intravenous immunoglobulin replacement because most of these patients, [due to] their previous history and because of the bispecific itself, will have a low level of IgG.

Oftentimes, that is associated with recurring infections, not just one episode. We will use [granulocyte colony-stimulating factor (G-CSF)] or growth factor support whenever we encounter a neutropenia of grade 3 or higher, and, in general, will be aware and [alert] for these potential infections because there's emerging data that suggests that there is a non-relapse mortality [risk] associated with bispecific antibodies, and that's primarily driven by infections. We want to make sure that we are aware of that complication and that we manage it promptly [or] prevent it if we can.

How can the current landscape of therapy be improved?

We run the risk of being complacent with our own success. We have most patients having a response, and most patients have a durable benefit from these treatments, but there are always improvements that we can look at. When the efficacy goes up, and when the bar continues to go up in terms of the efficacy, then there are also other things we look at. One of them is safety, and one of the emerging problems with using bispecific antibodies, much like we've seen with CAR T-cell therapy in its early days, is the relatively high prevalence of infections, in particular, severe infections, and how to manage those, how to preempt those, and how to prevent those. [These] are all open questions, and it is certainly a space where we can do better.

Another space where we can do better is identifying optimal biomarkers of response. Right now, when we are treating patients with bispecific antibodies, the way that we measure response is with a PET scan or with a radiographic imaging study. It's a good way to assess response, but it's certainly not optimal…. These immunotherapies work by activating the immune system to seek and destroy lymphoma cells, but that means that they artificially induce a lot of inflammation at the site of tumors. A PET scan will see that inflammation as a bright FDG-avid mass, and you could confuse that for progression of disease. We have encountered this case many times.

If you were to biopsy lesions in those patients, which we have done out of concern for progression, you would see [multiple] inflammatory cells in their benign lymphoma, and we call that pseudo-progression. One way to discriminate that [from a true progression] would be to identify a biomarker response that is not as fallacious as a PET scan. For example, if using MRD assessment, maybe in conjunction with PET scan assessments, would be a viable way to eliminate that problem. We do not know if MRD assessment is going to work in follicular lymphoma. There are some data [on that]. Others have done research in the same setting and in similar patient series, looking at the value of MRD. There could be a value [to using MRD assessments], but we simply need more data and more follow-up to ascertain that.

One last point is that we have [numerous] large, randomized trials in patients who are previously untreated with follicular lymphoma… that are going to treat patients for a long period of time because most of these trials have, in their design, an induction phase with 4 to 6 months of therapy, then a maintenance phase for another 18 months to 2 years. That adds up to over 2 years of therapy. When a treatment is so efficacious and the responses are so deep, are we entirely sure that every patient with follicular lymphoma needs 2 and a half years of therapy? With all the immunosuppression that comes with it and the infectious disease complications that we can see, perhaps we could optimize treatment and treat patients who need it [longer] and shorten treatments in those who do not. Can we use biomarkers to guide that decision-making? Those are all unanswered questions, but they clearly highlight an unmet need in the space.

Reference

Falchi, L. Novel immunotherapy combinations in indolent lymphoma. Presented at the Society of Hematological Oncology 2025 Annual Meeting; September 2-6; 2025; Houston, TX.