Stephen M. Ansell, MD, PhD

Question

What is your strategy for communicating with patients about the general efficacy of drugs that exist to treat classical Hodgkin lymphoma?

Answer

I think the first thing that’s always important to communicate to patients with newly diagnosed classical Hodgkin lymphoma is that our goal with therapy is to induce a complete remission that will, hopefully, be durable and will subsequently result in a long-term cure. I always caution trainees working with me not to say that it’s a good cancer, because I don’t think there’s such a thing. But on the other hand, it is a type of malignancy where our goal, for the majority of patients, is to get rid of the disease entirely, annd to hopefully have it stay that way for the long term. I think the important point to communicate to patients is that the hope and expectation with therapy is for a very good outcome. To achieve this, we need to balance dose intensity and toxicity. In other words, we want to make sure that we give full doses on time to optimize treatment efficacy, but also stop treatment as soon as possible to avoid long-term complications. In general, the efficacy of drugs in classical Hodgkin lymphoma is really good, but the bottom line is, we want to ensure that patients have the best outcome with the fewest side effects.

Question

Please explain how cell-free DNA (cfDNA) and/or circulating tumor (ctDNA) can be used to detect mutations in classical Hodgkin lymphoma. From your perspective, how far along is the science in this field for lymphoma, and is further research needed?

Answer

I think the science is progressing at an exceedingly rapid rate and this is a very exciting field. In classical Hodgkin lymphoma, the technology has allowed us to get to the point where circulating tumor DNA and cell-free DNA is readily detectable in plasma. Our biggest challenge is to utilize the information clinically and so further research is clearly needed. The reason for this further research is two-fold. Firstly, we’re not at the place where circulating tumor DNA or cell-free DNA can be a substitute for an excisional biopsy to make a definitive diagnosis, and so this techniques needs to be further validated. The second great challenge is, should we get to the point where we think that we can use this technique as a metric of response, whether we have tools that can allow us to intervene early with greater success To determine that will take research and randomized trials. All told, while there is a lot of enthusiasm for this approach, the challenge lies in the clinical application and validation of the technique and that’s predominantly where the research is needed.

Question

What is the role of natural killer cells in classical Hodgkin lymphoma, and how can treatment strategies incorporate them?

Answer

The potential for using natural killer (NK) cells in classical Hodgkin lymphoma is that natural killer cells are able to engage their targets without being dependent on the major histocompatibility complex (MHC) to present tumor-associated peptides or antigens. They can kill tumor cells with are poorly visible to the immune system, which is a very attractive part about natural killer cells. The interesting thing is that actually if one looks to see how many natural killer cells are present in biopsies of classical Hodgkin lymphoma, the numbers are actually quite low. It is not well understood why more natural killer cells are not present, and how one could attract more cells to the sites of disease? Strategies to use natural killer cells include recruiting them from the circulation, increasing their ability to target the tumor cells, and then use them as treatment. This would be similar to the way chimeric antigen receptor T-cells (CAR T-cells) are being developed in classical Hodgkin lymphoma. Natural killer cells with chimeric receptors are therefore a future prospect in Hodgkin lymphoma. This is certainly something that may be very useful in the future, but it’s still really early days in the development of this therapy.

Question

What are the most promising trials in classical Hodgkin lymphoma that are under way? Are there areas in which you feel more research should be directed?

Answer

The treatment of classical Hodgkin lymphoma has been a very exciting story over the last 5 or 10 years, with multiple new agents that are standard treatment in relapsed patients now making their way into frontline therapy. The U.S. Intergroup is developing a global, open-label, randomized phase 3 study comparing doxorubicin, vinblastine, and dacarbazine chemotherapy (AVD) in combination with brentuximab vedotin with AVD plus nivolumab as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (ClinicalTrials.gov Identifier: NCT03907488). This trial is just starting and will be very important to see how these new agents in combination perform in the frontline. In terms of future research, these new agents have had substantial success in the relapse and refractory patients and are now our standard of care, however, none of them are curative. Unfortunately, patients are now beginning to relapse after previous treatment with PD-1 blocking antibodiesand brentuximab vedotin, so new agents need to be developed. Therapies that target the innate immune system or the adaptive immune system is a promising strategy. CAR T cells are being developed in this space, but still have some challenges, and so there’s a lot of work still to be done.

Question

Autoimmunity-associated lymphoma: What are the trends in this space, and do you expect to see a rise in the incidence of this cancer subgroup? Could immunotherapies for other diseases/cancers affect incidence levels?

Answer

The response to this question is somewhat speculative as the data are quite limited. In part, this is due to an inadequate definition as to what an autoimmunity-associated lymphoma exactly is. Lymphomas that have developed in patients with diseases such as rheumatoid arthritis and other auto-immune diseases are often included in this group, but in those patients, the risk of lymphoma is actually associated with the treatment that was administered to treat the autoimmune disease rather than the autoimmune disease itself. In contrast, there is evidence for increased activation of the immune system that puts patients at risk for developing lymphoma. Infectious problems such as H Pylori or other kind of chronic infections can trigger lymphomas and these could be considered immune-mediated lymphomas. In general, when B-cells are rapidly proliferating in response to an immune stimulus, there is an increased risk of a genetic error. Now that immunotherapies are being used as treatment for various cancers there is a theoretical possibility that these treatments could trigger lymphoma. To date, we really don’t have clear evidence that immunotherapies for other diseases or cancers are increasing the incidence of lymphoma.

Question

Where is the field going for non-Hodgkin lymphoma (NHL) and T-cell lymphomas? What are exiting new and/or emerging therapies? Do you think chemotherapy will remain the standard frontline therapy in the near future?

Answer

There’s a lot of enthusiasm right now for chemotherapy-free approaches that utilize novel drug combinations rather than chemotherapy. However, I would recommend that we should proceed with caution. Chemotherapy plays an important role in rebooting the entire immune system and then allowing the immune system to come back in a more balanced fashion. Therefore, I think that chemotherapy still has a role because it allows us to modulate the immune system with the new drugs but gets rid of the very suppressive microenvironment around the tumor cell that is generated by the presence of the lymphoma. Personally I believe that chemotherapy is going to remain a part of what we do for patients with lymphoma and only somewhere in the future when we can target the chemotherapy better, will chemotherapy change. In terms of what’s exciting and new, I think one of the things I am most interested in and encouraged by is the approaches to engage macrophages and other parts of the adaptive immune system. These treatments target CD-47 and SIRPalpha, which provide ” don’t eat me” signals to prevent macrophages from phagocytosing tumor cells. This has already shown real promise, and I think that we’ll see a lot more of this therapy in the future.