Car rates

Smith discusses the changing lymphoma treatment landscape

Treatments for patients with Hodgkin’s and non-Hodgkin’s lymphoma have entered a new era with the advent of targeted and personalized therapies such as bispecific T cell activators (BiTE) and CAR T cell therapies.

“The future direction of lymphoma therapy is targeting lymphoma and the B cell signaling pathway,” said Leslie Smith, DNP, RN, APRN-CNS, BMTCN, AOCNS. “Most lymphomas are B-cell [lymphomas] and it really explores what’s going on at the cellular level, how the lymphoma cell communicates, so [we’re seeing] highly 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 lymphoma treatment landscape changed?

Black-smith: Traditionally, Hodgkin’s and non-Hodgkin’s lymphomas have been treated with chemotherapy; Hodgkin receives chemotherapy and radiation therapy [and] non-Hodgkin is treated with chemotherapy and then monoclonal antibodies, which changed the paradigm [and improved] survival of non-Hodgkin’s patients in the late 1990s.

Now, lymphoma treatments focus on the genetic drivers of the disease and therefore the genetic drivers drive the signaling pathway. [We must then ask] what are the signaling pathways of the lymphoma cell that alter the way the immune system or the lymphomas or the lymphocyte interacts with its environment and becomes 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 medicines, [such as] immunomodulatory drugs lenalidomide [Revlimid] and thalidomide [Thalomid]and the BTK inhibitors ibrutinib [Imbruvica]acalabrutinib [Calquence], [and zanubrutinib (Brukinsa)]. Plus, checkpoint inhibitors made a huge difference in relapses [or] refractory disease.

You can’t discuss [lymphoma] not to mention the CAR T cells, which, although they showed excellent response rates, were not [inducing] remission for many patients.

Thus, there are several drugs – BTK inhibitors, IMids, PI3K inhibitors – that target various parts of the signaling pathway that lead to the development of lymphoma and [drive the] prevention of apoptosis.

How do BiTES play a role in the treatment of lymphoma? What data support their use in the clinical setting?

BiTE, such as blinatumomab [Blincyto]are important to talk about. [They] have shown early success in conferring remission. Blinatumomab specifically had a lot of toxicities in trials and many lymphoma patients were discharged early due to neurotoxicity and they had grade 3/4 cytokine release syndrome [CRS].

Additionally, there was no sustained response, so patients relapsed within months of receiving the drug. There are now new BiTEs, REGN1979 also called odronextamab and glofitamab. These showed better response rates with lower toxicity – patients had no neurotoxicity…or CRS. The debate is how to dose or administer the drug. Should it be a weekly fixed dose infusion or should it be an escalating dose infusion? [Investigators are] I’m still trying to figure this out, but [early efforts are] showing some promise of getting patients into remission.

Interestingly, these drugs show a better response in indolent lymphomas, particularly follicular lymphoma, rather than in more aggressive lymphomas. There is still work to be done to study these drugs, but they show promise.

Could you discuss the evolving role of CAR T-cell therapy in the treatment of lymphoma patients? What benefits and what limits can we observe regarding this therapeutic approach? What do you think of the integration of CAR T-cell therapy in the first lines of treatment?

CART-[cell therapy] has been great medicine for relapses [or] refractory non-Hodgkin’s lymphoma, until progression-free survival is confirmed. However, similar to what we see 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. Thus, any CAR T cells that remain in the patient’s body and go unnoticed have nothing to attack. Now the malignant cell has transformed to be able to survive.

For patients, the progression-free survival rate in lymphoma for CD19-[targeted] CAR T cells, which are primarily what is now approved for lymphoma, are 30% to 50% [PFS rate]. At NIH, we are looking at CAR T cells that target 2 antigens, such as CD19 and CD20; we are trying to target 2 antigens on the surface of the receptor itself.

There are [the question of] should we pair CAR T cells with checkpoint inhibitors, because CAR T cells also get depleted like our normal immune system T cells and checkpoint inhibitors can take care of that. TRUCKs, which stand for T cells redirected to universal cytokine destruction, [are armored CAR T cells]. They confer genes to help stimulate a large cytokine response in the immune system to kill malignancy. [Approximately] half of the patients will get a lasting recovery, but when it comes to initial use, I think it’s the same discussion hematologists have with the leukemia population. Should we use them as a priority, reserve them for relapses [or] refractory, should they be a terminal treatment since the patient is receiving CAR T, does he need a transplant or should he be a bridge to the transplant?

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

But I think CAR T is promising and there was a new [therapy] just approved for mantle cell lymphoma [brexucabtagene autoleucel (Tecartus)] who got early approval [which is promising because] Mantle cell lymphoma is a very rare and aggressive type of lymphoma. I think there is a lot of room for CAR T but they still manipulate 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 some lymphoma patients?

I think so. The transplant is not without risk. First you need to find a donor – does a patient have a family member who is a related donor, because a related donor is better if they have the human leukocyte antigen [HLA] corresponding to.

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

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

At what stage is the disease? Did the patient present at stage 3 or 4 of the disease? What type of lymphoma do they have? Do they have T cell lymphoma [which] tends to be more aggressive than a B lymphocyte? What is the patient’s age? When I was in Ohio I was caring for a patient he was 90, maybe 91, but he was still working full time, he played golf every day, he had lymphoma and he wanted everything [treatment wise]. And he could take it because chronologically he was 92 years old [years]but he was more like 50 years old [years] because he was going around in circles around the nurses. I think it depends on the age of the patient and their comorbidity status. Do they suffer from renal insufficiency or hepatic insufficiency, are they diabetic?

These are things to consider, as well as asking patients what they want. It is sometimes difficult to separate what the patient [wants] and what the family wants. I think the stage of the disease, their comorbidities, the age of the patient, these are considerations for the type of treatment to follow. Now that we have oral medications for lymphoma, these are a good option for [older] patients who do not want aggressive treatment.