Smith Discusses Evolving Landscape of Lymphoma Treatments

Leslie Smith, DNP, RN, APRN-CNS, BMTCN, AOCNS

Treatments for patients with Hodgkin and non-Hodgkin lymphoma have entered a new era with the advent of targeted and personalized therapies such as bispecific T-cell engagers (BiTEs) and CAR T-cell therapies.

“The future direction for lymphoma treatment is targeting the lymphoma and the signaling pathway of the B cell,” Leslie Smith, DNP, RN, APRN-CNS, BMTCN, AOCNS, said. “Most lymphomas are B-cell [lymphomas] and that’s really drilling down into what is happening at the cellular level, how the lymphoma cell is communicating, so [we’re seeing] very targeted therapy.”

In an interview with Oncology Nursing News®, Smith, a clinical nurse specialist at the National Institutes of Health (NIH), discussed treatment selection in this patient population and how new therapies are changing the lymphoma landscape.

Oncology Nursing News®: How has the landscape for the treatment of lymphoma changed?

Smith: Traditionally, both Hodgkin and non-Hodgkin lymphoma have been treated with chemotherapy; Hodgkin gets chemotherapy and radiation therapy [and] non-Hodgkin is treated with chemotherapy and then monoclonal antibodies, which changed the paradigm [and improved] survival for patients with non-Hodgkin in the late 1990s.

Now, lymphoma treatments are focused on the genetic drivers of the disease and as a consequence the genetic drivers lead to the signaling pathway. [We must then ask] what are the signaling pathways of the lymphoma cell that are altering the way the immune system or the lymphomas or the lymphocyte is interacting with its environment and becoming a lymphoma cell.

If we can target those pathways, it becomes targeted therapy, as opposed to general chemotherapy or radiation therapy. These include some traditional drugs, [such as] the immunomodulatory drugs lenalidomide [Revlimid] and thalidomide [Thalomid], and the BTK inhibitors ibrutinib [Imbruvica], acalabrutinib [Calquence], [and zanubrutinib (Brukinsa)]. In addition, checkpoint inhibitors have made a huge difference in relapsed [or] refractory disease.

You can’t have a discussion about [lymphoma] without talking about CAR T cells, which even though they have shown great response rates it has not been [inducing] remission for a lot of patients.

So, there are multiple drugs—BTK inhibitors, IMids, PI3K inhibitors—that target various parts of the signaling pathway that drive the development of lymphoma and [drive the] prevention of apoptosis.

How are BiTES playing a role in lymphoma treatment? What data support their use in the clinical setting?

BiTEs, such as blinatumomab [Blincyto], are important to talk about. [They] have shown early success as far as conferring remission. Blinatumomab specifically had a lot of toxicities in the trials and many patients with lymphoma came out early because of the neurotoxicity and they had grade 3/4 cytokine release syndrome [CRS].

In addition, there was not a sustained response, so patients relapsed within a few months after receiving the drug. There are newer BiTEs now, REGN1979 also called odronextamab, and glofitamab. Those have shown better response rates with lower toxicity—patients did not have neurotoxicity…or CRS. The debate is how to dose or administer the drug. Should it be a weekly infusion on a flat dose, or should it be an escalating dose type of infusion? [Investigators are] still trying to figure that out, but [early efforts are] showing some promise with getting patients in remission.

Interestingly, these drugs are showing better response in indolent lymphomas, especially follicular lymphoma, rather than the more aggressive lymphoma. There is still more work to be done looking at these drugs, but they are showing some promise.

Could you discuss the evolving role of CAR T-cell therapy in treating patients with lymphoma? What benefits and limitations are we observing regarding this treatment approach? What are your thoughts on incorporating CAR T-cell therapy into earlier lines of treatment?

CAR T-[cell therapy] has been a great drug for relapsed [or] refractory non-Hodgkin lymphoma, as far as confirming progression-free survival. However, similar to what we’re seeing in leukemia, [the] cancer is smart, it outsmarts us all the time. It changes its antigen receptors on the surface of the malignant cell and then we have loss of antigen and so any CAR T cells that are remaining in the patient’s body that are there and go unnoticed don’t have anything to attack. Now the malignant cell has transformed itself to be able to survive.

For patients, the progression-free survival rate in lymphoma for the CD19-[targeted] CAR T cells, which is mostly what’s approved now for lymphoma, is 30% to 50% [PFS rate]. At NIH, we’re looking at CAR T cells that target 2 antigens, such as CD19 and CD20; we’re trying to target 2 antigens on the surface of the receptor itself.

There’s [the question of] should we pair CAR T cells with checkpoint inhibitors because the CAR T cells also get exhausted, like the T cells in our normal immune system and the checkpoint inhibitors may take care of that. The TRUCKs, which stands for T cells redirected towards universal cytokine killing, [are armored CAR T cells]. They confer genes to help stimulate a big cytokine response within the immune system to kill the malignancy. [Approximately] half of patients will get a sustainable recovery, but as far as being used upfront, I think that’s the same discussion that hematologists have with the leukemia population. Should we use them first, reserve them for relapsed [or] refractory, should they be a terminal treatment in that patient gets CAR T, does it need a transplant, or should it be a bridge to transplant?

CAR T has a lot of [adverse] effects. An older patient may have more difficulty because non-Hodgkin lymphoma is a disease of patients older than 60 [years], maybe in their 70s. It is also very expensive, remaining about a half a million dollars to get this treatment and I think most places still require a caregiver to be with the patient during the initial few months. That can be a challenge for some [individuals] who have children, are working, or maybe do not have family and friends who are available.

But I think CAR T is showing promise and there was a new [therapy] just approved for mantle cell lymphoma [brexucabtagene autoleucel (Tecartus)] that got early approval [which is promising because] mantle cell lymphoma is a very rare, aggressive type of lymphoma. I think there’s a lot of room for CAR T but they're still manipulating the CARs to make a more effective response.

In your opinion, has CAR T-cell therapy impacted the suitability of autologous stem cell transplantation for certain patients with lymphoma?

I think it has. Transplant is not without risk. First you must find a donor—does a patient have a family member who is a matched-related donor because a match-related doner is better if they have the human leukocyte antigen [HLA] matching.

In older patients, transplant can sometimes be fatal. There’s the sequelae of transplant years down the line where patients are still prone to infection and secondary malignancies as time goes on over the general population. Perhaps CAR T for an older patient would be a better choice than transplant, especially since we have allogeneic CAR T cells, where you can get CAR T can come from a donor, and you don’t have to worry so much about the HLA matching as much as you do with a stem cell transplant. For some patients CAR T may be a better option then a transplant.

What are some important considerations when selecting a treatment regimen for a patient with lymphoma?

What stage is the disease? Did the patient present at a stage 3 or 4 disease? What type of lymphoma do they have? Do they have a T-cell lymphoma [which] tends to be more aggressive than a B cell? What is the age of the patient? When I was in Ohio, I took care of a patient he was 90 years old, maybe 91, but he was still working full time, he was playing golf every day, he had lymphoma and he wanted everything [treatment wise]. And he could take it because chronologically he was 92 [years], but he was more like 50 [years] because he would run around in circles around the nurses. I think it depends on the age of the patient and their comorbidities status. Do they have some renal failure or liver failure, are they a diabetic?

Those are things to consider, as well as asking the patients what they want. It’s hard to separate out sometimes what the patient [wants] and what the family wants. I think the stage of the disease, their comorbidities, the age of the patient, those are considerations for what type of treatment to go for. Now that we have oral drugs for lymphoma, those are a good option for [older] patients that may not want aggressive treatment.