Exploring T-Cell–Directed Therapies for Indolent B-Cell Lymphoma

Pharmacy Times interviewed Sonali Smith, MD, chief of the Section of Hematology/Oncology at University of Chicago, on her presentation at the SOHO 2024 Annual Meeting on T-cell directed therapy for indolent B-cell lymphoma. Smith discussed T-cell–directed therapies, highlighting bispecific agents and CAR T-cell therapy.

Pharmacy Times: How do T-cell directed therapies work in the context of indolent B-cell lymphomas?

Sonali Smith, MD: When we think about T-cell–directed therapies, they really fall into 2 classes that are currently FDA approved. The first is antibody-based therapy, and the other is T-cell cellular therapy. For the talk that I presented today, I discussed some of the newer antibody technology that includes bispecific agents, as well as CAR T-cell therapy, specifically for follicular lymphoma. The way that these T-cell therapies work is a little bit different depending on the specific product, but in general, I discussed bispecific agents, which are essentially CD20 by CD3 binding agents that engage T cells to help eliminate malignant B cells. I also discussed CAR T-cell therapy, where T cells are harvested autologously from the patient and then engineered to be reintroduced to the patient and have an anti-lymphoma effect.

Pharmacy Times: What are some of the most prominent T-cell directed therapies for indolent B-cell lymphoma currently being used in practice or investigated for use?

There are several different T-cell therapies that are being used in indolent lymphomas. Image Credit: © pimmou - stock.adobe.com

Smith: There are several different T-cell therapies that are being used in indolent lymphomas. The first is, of course, just simple antibodies, but what I really focused on today were bispecific antibodies, and this includes 2 FDA approved agents in follicular lymphoma, mosunetuzumab (Lunsumio;Genentech) and epcoritamab (Epkinly, Genmab US, Inc). But I also discussed odronextamab (Ordspono; Regeneron Pharmaceuticals, Inc) and then very slightly on glofitamab (Columvi;Genentech), where there are minimal data in the indolent subtypes of lymphoma. I also discussed CAR T-cell therapy, where there are now 3 FDA approved products, including axicabtagene ciloleucel (Yescarta; Kite Pharma, Inc), tisagenlecleucel (Kymriah; Novartis Pharmaceuticals Corporation) and lisocabtagene maraleucel (Breyanzi; Juno Therapeutics, Inc) .

Pharmacy Times: What are some of the FDA-approved therapies available, or other therapies being investigated in clinical trials for indolent B-cell lymphoma?

Smith: There are 2 FDA approved bispecific agents that are now available for patients with relapsed and refractory follicular lymphoma. One is mosunetuzumab and the other is epcoritamab. They have a couple of shared features and that they are both CD20 by CD3 designed agents, but there are some structural differences as well as a couple of other clinical differences. So for mosunetuzumab, this has an FC portion that has been engineered to minimize some of the toxicity and the epitope portion of it for the CD20 part shares the same area of CD20 as rituximab. Mosunetuzumab is given in a ramp-up phase for the first cycle, and then every 21 days up to 17 cycles, with a response directed pause after cycle 8.

Epcoritamab is a is also a CD20 by CD3 by specific antibody, and it also has an FC-engineered portion where specific mutations have been introduced, again to minimize potential toxicity of the bispecific agents. Epcoritamab is available primarily as subcutaneous administration, and it also has a stepped up dosing, or ramp up phase, which is designed to minimize some of the key side effects that we see from these agents, such as cytokine release syndrome. The stepped up dosing is given with dexamethasone to help minimize some of those initial toxicities, which are seen primarily in cycle 1 and cycle 2. And I should also add that mosunetuzumab also has steroid premedication for the first 2 cycles.

Pharmacy Times: What have data shown regarding the efficacy of T-cell–directed therapies in indolent B-cell lymphomas?

Smith: So the efficacy of T-cell–directed therapies in the form of bispecific antibodies is very exciting. The response rates are around 80% with a complete response rate of around 60%, and many of these responses appear quite durable for mosunetuzumab, which has a limited duration of administration. There is currently about a 3 year follow up, and many of the responses appear very durable for the other antibodies. I think time will show, but I'm very optimistic.

Pharmacy Times: What are the most common adverse effects (AEs) from these drugs, and how are these AEs managed?

Smith: So the most common [AEs] from the bispecific antibodies are primarily in the first [cycle]—there are several that are early, so in the first cycle or 2, and others that are persistent throughout the duration of treatment. So focusing first on the early toxicity, this is mainly related to T-cell engagement and activation, and takes the form of cytokine release syndrome. This can be manifested as fevers, hypotension, and very rarely, there is a small amount of confusion that can occur for patients. This is very different than what is seen with CAR T-cell therapy, [as it’s] much lower in frequency and also in severity. But to mitigate the cytokine release syndrome, it's really important that the first few doses are given by an experienced center, or at least a prepared center, so that those [AEs] can be obviated. The longer term [AEs] that can occur are the risk for infection, prolonged cytopenia, and hypogammaglobulinemia.

Pharmacy Times: What are some of the treatment challenges when treating indolent B-cell lymphomas with T-cell directed therapies?

Smith: One of the biggest challenges is that there is a bit of a learning curve with managing cytokine release syndrome. In order to safely deliver this for the first cycle or 2, it's important to have an educated team on hand, an educated patient, to have tocilizumab [Actemra; Genentech, Inc] or other agents that can help manage the cytokine release syndrome, and to know when and how to use steroids. There is a wonderful article published in Blood by a panel of experts that helps guide the safe delivery of these agents in the community setting.