Outlining Ongoing Clinical Developments in Treatment for Rare Lymphomas

CancerNetwork® spoke with Neha Mehta-Shah, MD, MSCI, associate professor in the John T. Milliken Department of Medicine in the Division of Oncology at the Washington University Medical School in St. Louis, MO, about ongoing clinical trials currently evaluating treatment in patients with rare lymphomas that she believes are promising.

Mehta-Shah began by suggesting that many agents being assessed for this patient population appear promising, but initially highlighted studies in T-cell lymphomas. This group of studies comprised the development of PI3K and EZH2 kinase inhibitors, which have consistently shown efficacy across numerous types of T-cell lymphomas, and have few options for standard treatment.

Furthermore, she mentioned the development of antibodies for patients with KIR₃DL₂ alterations, which displayed durable responses and bolstered quality of life in a group of patients who typically suffer disease- and treatment-related impairments to quality of life.

Mehta-Shah further touched upon a US intergroup study to evaluate immunotherapy, particularly nivolumab (Opdivo) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) in patients with Hodgkin lymphoma, which sought to mitigate adverse effects and long-term health care events. The trial ultimately showed that nivolumab-AVD enhanced progression-free survival vs brentuximab vedotin (Adcetris)-AVD.

Highlighting a need to de-escalate therapy to mitigate adverse effects and maintain or improve quality of life, she highlighted an additional intergroup study assessing immunotherapy plus chemotherapy in earlier lines of therapy, with a similar focus on survival, survivorship, and quality of life.

Transcript:

There are many agents currently being studied that are promising in rare lymphomas, [which] I will break down into certain categories. One group of studies, the studies in T-cell lymphoma, which is an area I am particularly passionate about, and we have been excited about the development of both PI3K inhibitors and EZH2 inhibitors in T-cell lymphomas. The studies now consistently across multiple drugs in the same class, for both types, seem to show that these drugs are efficacious, even when chemotherapy or other standard agents have not been efficacious. These patients have particularly few options for standard treatment, nationally and internationally, so that is one group of therapy that we are [particularly] excited about for rare diseases like cutaneous T-cell lymphoma.

There are studies exploring those classes of medicines which are exciting, but then in addition, there have been studies looking at novel antibodies, particularly [those] against KIR₃DL₂ which have shown durable remissions with improved quality of life for these patients who suffer high impairment in their quality of life when due to both their disease and in some situations, due to their treatment. We are excited about this novel class of medicines in that arena.

The other area that we are excited about is the use of immunotherapy in Hodgkin lymphoma, which is also a [particularly] rare lymphoma, but a significant number of people with Hodgkin's lymphoma are young adults. As we have gotten better at treating and curing some of these patients, we are trying to develop treatments that have [fewer adverse] effects long term and do not increase their risk of other health care events like heart attack, strokes, breast cancer, and other cancers. The development of immunotherapy earlier in the course of therapy [in the phase 3 S1826 trial (NCT03907488)], which was a large US intergroup effort to demonstrate that nivolumab-AVD may be beneficial, at least with the progression-free survival benefit over brentuximab vedotin-AVD, that is exciting.¹

How [do we] now de-escalate that therapy and potentially give less chemotherapy or monitor the quality of life to decrease long-term [adverse] effects, is one of the goals. There is currently a US intergroup study [NCT06745076] looking at patients who have early-stage Hodgkin lymphoma incorporating brentuximab-vedotin and nivolumab earlier in their course of therapy.² Similarly, that is measuring survival, survivorship, as well as quality of life.

References

1. Herrera AF, LeBlanc M, Castellino SM, et al. Nivolumab+AVD in advanced-stage classic Hodgkin’s lymphoma. N Eng J Med. 2024;391(15):1379-1389. doi:10.1056/NEJMoa2405888
2. Personalized reduction of chemotherapy intensity through ctDNA evaluation for the treatment of patients with advanced Hodgkin lymphoma. ClinicalTrials.gov. Updated March 10, 2025. Accessed April 11, 2025. https://tinyurl.com/2vs2hf5r