LaCasce Shares Hopes for 2024, Highlighting Advancements Across Lymphomas

Ann LaCasce, MD, MMSc

Heading into 2024, the field of lymphoma has experienced a number of advancements that offer hope and can improve outcomes for patients. With technologies like bispecific antibodies and circulating tumor DNA (ctDNA), personalized and targeted therapies are coming more into play for the treatment of patients.

Bispecific antibodies are emerging with the hopes of moving away from bendamustine as their ability to simultaneously target multiple cancer-fighting pathways may be more effective and potentially less toxic than traditional chemotherapy.¹ Additional combinations with other drugs, including lenalidomide (Revlimid) and polatuzumab vedotin-piiq (Polivy), rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP), are also showing promise, setting the stage for a new era of frontline therapy in lymphoma.²

ctDNA is another development that has been changing the game for the management of lymphoma as it allows clinicians to track disease progression and predict patient outcomes with unprecedented accuracy.³ Through the analysis of fragments of cancer DNA circulating in the bloodstream, ctDNA can aid in tailoring treatment plans for individual patients, monitor response to therapy, and help identify patients who may benefit from less intensive treatment.

These advancements, as well as many more, are transforming the treatment landscape for patients with lymphoma as they show the potential to replace older and less effective options that are currently available, as well as the ability to tailor therapy to each individual's unique needs.

In an interview with Targeted Oncology^TM, Ann LaCasce, MD, MMSc, director of the Dana-Farber/Massachusetts General Brigham Fellowship in Hematology/Oncology and chair of the Lymphoma Research Foundation Scientific Advisory Board, delved into the surge of innovations with personalized medicine, advanced technologies, and novel agents for the treatment of patients with lymphomas.

Microscopic images of red blood cells as a result of leukemia: © AkuAku - stock.adobe.com

Targeted Oncology: Can you discuss the role of bispecifics for the treatment of lymphomas?

LaCasce: For bispecifics, we're starting to see some upfront data in the frontline, particularly follicular lymphoma, as a single-agent or in combination with lenalidomide. I think this is where the field is heading in the next year and beyond. We're going to see, hopefully, the death of bendamustine, particularly in the frontline, in the hopefully near future. I think we've learned a lot about bendamustine being a problem during the pandemic given its effects on lymphocytes, T cells, and immunity.

We also saw a longer-term follow-up in the relapsed and refractory setting in multiple different lymphomas, both follicular in combination with polatuzumab vedotin in mantle cell and single-agent in chimeric antigen receptor [CAR] refractory [diffuse large B-cell lymphoma]. I think these agents are here to stay and also are moving up front in combination with like Pola-R-CHP in higher-risk patients. Hopefully, we're going to be curing more patients upfront with DLBCL.

For Hodgkin [lymphoma], we saw some data for nivolumab/[doxorubicin, vinblastine, and dacarbazine (AVD)] in elderly patients. [Nivolumab]/AVD vs [brentuximab vedotin (Adcetris) plus AVD (Bv-AVD)] from the SWOG S1826 study [NCT03907488] that looks quite dramatic in terms of both the benefit and progression-free survival. I think that's going to become the standard. We look forward to seeing the publication of the whole study, but I think in 2024, [nivolumab]/AVD will be standard frontline therapy for advanced stage Hodgkin lymphoma.

We also saw some other data looking at combinations like replacing vinblastine with brentuximab, so nivolumab, adriamycin, brentuximab, dacarbazine data, so we're going to see more of those. I think those are single-arm studies, but I think we'll probably have a randomized study comparing that to [nivolumab]/AVD in the future. Maybe it won't be for 2024, but I think that's where we're headed.We have a big, randomized study that's ongoing and looking at if early-stage patients also benefit from novel agents, can we identify who they are, [and] are they using PET?

I think we're [also] going to see a lot more circulating tumor DNA. There were a bunch of studies looking at using that in conjunction with the end of treatment PET scans to predict outcomes in patients. Looking at disease in the [central nervous system] at baseline, I think that's another direction that cell-free DNA is moving. I think we're—both in terms of therapeutics and in predicting what patients—going to do well. We're moving forward rapidly and in that field. For [chronic lymphocytic leukemia], [we are] using [minimal residual disease (MRD)]-directed therapy, time-limited treatment, [and] lots of studies are ongoing. We have so many good drugs in that field.

For mantle cell lymphoma, we still need the results of the TRIANGLE study [NCT02858258]. Hopefully that's going to come out in 2024. We need to finish the US intergroup study, which is a study asking, is there a benefit to autologous transplant in MRD-negative patients after initial therapy? But once we've accrued that, it'll be interesting to see the results. I think the TRIANGLE study is going to have us move away from transplant and incorporate [Bruton tyrosine kinase (BTK)] inhibitors upfront.

Then for patients who’ve already been treated and then relapsed, I think BTK plus venetoclax [Venclexta]. The SYMPATICO trial [NCT03112174] was presented in the late-breaking abstracts at [the 2023 American Society of Hematology (ASH) Annual Meeting]. Last year, we had a lot of new stuff and this year, it's sort of taking it to the next step. We're starting to see all that data and studies move into the clinic.

What emerging technologies or innovative therapies do you expect may play a significant role in management moving forward?

I think the circulating tumor DNA is probably one of the big ones. Not only the end of treatment, but can we use it to predict to maybe give less treatment. It's important, not only in non-Hodgkin lymphoma, but also in Hodgkin lymphoma. I think that's going to continue to be refined and become more mainstream. There are some new CAR T-cell technologies. I think that's going to be interesting using novel targets, targeting 2 antigens, or having new ways of manufacturing CAR T that can be done onsite and by individual centers. I think we're going to see more of that.

How do you anticipate the landscape of immunotherapy continuing to evolve?

In lymphoma, we've been using immunotherapy in the form of rituximab now for several decades, so we're pretty lucky. I think we're going to be moving from beyond just standard monoclonal antibodies to bispecific antibodies [and]cellular therapies, which I would consider a form of immunotherapy. The checkpoint inhibitors that are so important in solid tumors are important in Hodgkin lymphoma, and maybe primary mediastinal [lymphoma]. But our immunotherapy looks a little bit different from solid tumors. I think that's where we're headed in almost all lymphomas.

We still have a lot of work to do in T-cell lymphoma. There was a little bit of data at ASH looking at some newer drugs. There is this drug called valemetostat [Ezharmia], and we saw more data from that and hope that that will be approved soon. This is emerging as 1 of our big [agents]. It's a rare but unique set of diseases where the biology is quite variable from 1 disease to another. We need more work there. I'm predicting that it will be approved next year so that we can start to use it in the clinic, and then move it upfront and combine it to hopefully do better for those patients.

Are there any subtypes of lymphoma that you believe may get increased attention this year?

I think across B-cell lymphomas, we're going to see just more bispecific-driven combinations. Fortunately for lymphoma, the bispecifics are applicable to many subtypes of lymphoma, so I think it's kind of across the board. In T-cell lymphoma, again, we hope to see some advances, but we're lagging.

Are there any challenges or hurdles that the oncology community might face when implementing these predicted advancements?

One is accessibility and price. Two are the bispecifics we're using in the referral academic centers. But there is a lot of variability in how they're administered and when you anticipate toxicity. I think it's been hard for the community to start using these drugs. I think that is a barrier. There are some publications coming out soon giving guidance on how to use these.

I hope that that will become more widely disseminated, but it is a huge barrier at this point because CAR T is expensive. Again, it has to be done at referral centers. That is a barrier for many patients. All of our novel drugs, the oral drugs, the targeted agents, are expensive. It's 1 thing to get coverage for intravenous therapies that we give in the clinic, but to get oral drugs is a huge issue. We really need to work on that as a community. It's true across all diseases. We keep developing these amazing options but if our patients can't afford them, what are we doing?

How may personalized or precision medicine continue to impact the lymphoma space?

We continue to identify subsets within diseases, like diffuse large B-cell lymphoma which has many different subtypes within it. Over time, we're seeing therapies that are differentially active in certain subsets, looking at pathways that are important, and I think that's where we're headed in all of these diseases.

In mantle cell lymphoma, TP53-mutated disease, we know that those patients don't do well with transplant or do worse in general. We're tailoring our therapies based on that information. That's 1 way that we personalize, by understanding the genomics of the disease. Then, we are personalizing by looking at minimal residual disease and using it to identify who's in remission and who needs more treatment. I would consider that to be personalized also from the beginning, then as we go through.

Are there any ways that you see the integration of artificial intelligence (AI) influencing this space moving forward?

I think AI will be critical in understanding all this data that we get back scientifically from our scientists who are analyzing all these different molecular aspects of transcriptome. All this amazing work has helped us to understand biology and disease. I think AI is going to help us to streamline and analyze huge amounts of data.

I also hope that AI will help us to look at real-world clinical data. I think that we know that clinical trials enroll a particular subset of patients. Patients who are usually healthier can have time to wait to get on a trial, and the real-world data gives us a lot of additional information, both on how patients do and what patients are offered in the community, and being able to understand what's going on out there outside of artificial practices where our patients may not reflect what's really going on. Being able to harness all that data is hugely important, and AI could help us do that.

REFERENCES:

1. Falchi L, Vardhana SA, Salles GA. Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities. Blood. 2023;141(5):467-480. doi:10.1182/blood.2021011994

2. Friedberg JW, Thompson CA, Trneny M, et al. Health-related quality of life (HRQoL) in patients with diffuse large b-cell lymphoma (DLBCL) treated with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the phase III POLARIX study. Blood. 2022;140 (1): 6623–6626. doi:10.1182/blood-2022-157761

3. Roschewski M, Rossi D, Kurtz DM, Alizadeh AA, Wilson WH. Circulating Tumor DNA in Lymphoma: Principles and Future Directions. Blood Cancer Discov. 2022;3(1):5-15. doi:10.1158/2643-3230.BCD-21-0029