Novel Approaches Under Exploration Across Lymphoma Subtypes

Erin Reid, MD

To continue the progress of treatment for patients with T-cell lymphoma, B-cell lymphomas, and Burkett lymphoma, research efforts must be focused on further defining disease subtypes and determining the most efficacious regimens, explained Erin Reid, MD.

“I encourage providers to seek out clinical trials for their patients because this is the only way that we can continue to make improvements,” said Reid. “In general, for hematologic malignancies, and certainly for lymphomas, these are all rare diseases. The best way we're going to move forward is by collaborating and including patients as much as possible into either prospective or retrospective clinical trials and registries.”

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Reid, a hematologist and professor of medicine at University of California, San Diego (UCSD) Health, discussed the treatment advances across lymphomas and the remaining questions that need to be answered with further research.

OncLive: Could you provide an overview of the current state of lymphoma treatment?

Reid: Within the peripheral T-cell lymphoma (PTCL) world, for example, there were the ECHELON-2 data, which demonstrated a significant benefit in progression-free survival (PFS), as well as overall survival (OS), with the addition of brentuximab vedotin (Adcetris) to the CHP regimen, which is basically CHOP without vincristine. This was a randomized trial comparing brentuximab vedotin plus CHP with CHOP. This was one of the biggest updates that we had in the T-cell lymphoma world in a very long time.

There was an update at the 2019 ASH Annual Meeting on Burkitt lymphoma, looking at a subset of patients with Burkitt lymphoma who have relapsed central nervous system (CNS) disease and the different upfront regimens that are associated with improved chances of not having CNS relapse. The important thing about Burkitt lymphoma is that your first shot [at treatment] is your best shot. If we don't get rid of [the disease] during the first round, it's very hard to get people into complete remission on subsequent therapies. There are a lot of exciting things coming down the pike for both B-cell and T-cell lymphomas that are in development.

Before ECHELON-2, what was the standard of care for patients with T-cell lymphoma? Why does brentuximab vedotin work well in this patient population?

Traditionally, standard-of-care therapy for patients with T-cell lymphoma has been CHOP or CHOP-like regimens. You could argue that ECHELON-2 is still a CHOP-like regimen because it has that backbone, but because brentuximab vedotin is a monoclonal antibody with a drug conjugated to it, it's adding the ability to more precisely deliver a toxin to the tumor cells than we can do with systemic chemotherapy. [The addition of brentuximab vedotin] has been demonstrated to be efficacious in Hodgkin lymphoma, initially with relapsed Hodgkin lymphoma and then in the upfront setting, as seen in the ECHELON-1 trial.

In T-cell lymphoma, we have various types of PTCL. They each have different risk factors that are associated with likelihood of long-term PFS with brentuximab vedotin. This is the first time we've ever seen doubling or more than doubling of PFS and OS [with a therapy compared with standard treatment].

How do you determine the subtype of lymphoma?

Your initial diagnostic workup with pathology would include the subset of what type of T-cell lymphoma you're dealing with. That [would determine] whether you would consider doing first-line consolidation with autologous stem cell transplant. There are some subtypes that have better risk profiles, and there is a question of whether [first-line consolidation and transplant are] necessary and other subtypes in which [first-line consolidation with transplant] seems to be the only way to have a chance at a prolonged PFS.

What markers are used to indicate whether a patient has a more aggressive disease?

The one with the best profile for T-cell lymphomas are the ALK-positive anaplastic large-cell lymphoma. The ALK-negative anaplastic large cells have poor survival outcomes. ALK protein expression is one of the important ones to check for. There are a lot of other subtypes of T-cell lymphoma that don't do as well [as ALK-positive anaplastic large-cell lymphomas], in general.

How are PI3K inhibitors used in lymphoma?

PI3K inhibitors have been important in general for lymphomas, and they had some improvement in the relapsed/refractory setting for peripheral T-cell lymphomas. The PI3K inhibitors demonstrated, both in that setting as well as in relapsed/refractory indolent B-cell lymphomas, improvement in response rates.

Are there any toxicity challenges with PI3K inhibitors?

The problem is that, from PI3K inhibitors, a lot of patients will have issues with gastrointestinal toxicity—mainly diarrhea. It may or may not be feasible to give [PI3K inhibitors], depending on the comorbidities for patients with T-cell lymphoma or follicular lymphoma who might be receiving this drug.

Some patients are coming in very frail at the time of the presentation of their lymphoma. It's very difficult to give them something that's going to affect the nutritional status and the ability to keep down fluids or have enough fluids in the body. That's been one of the more limiting things, but there have been improvements in the supportive care profile for PI3K inhibitors that have made it more feasible. They're definitely a very active category of drugs that we can use for B-cell and T-cell lymphomas in the relapsed/refractory setting.

What are the next steps of research for T-cell and B-cell lymphomas?

We still have room for improvement. In the lymphoma world, we always say that, stage for stage, the T-cell lymphomas are harder to cure than the B-cell lymphomas in general. There are some B-cell lymphomas that are difficult [to cure] as well, but we have a lot more room for improvement on T-cell lymphoma.

In the frontline setting, brentuximab vedotin has made the biggest difference that we've seen with anything that's been tested. There are a lot of other active drugs out there. It's not that there's nothing to use. We have a lot of things to use, but we need to find the right combinations. There is promising stuff coming down the line with respect to more immunotherapy-related treatments, such as like what we have been seeing with B-cell lymphomas, but we're not there yet.

How do you determine what agents to use when treating patients?

It's going to depend on the subtypes and the nuances. Generally, we're looking at the patient’s comorbidities and the safety profiles of these particular agents. That will likely determine what one is going to use in that situation.

Moving to Burkitt lymphoma, what are some of the most potent agents being used?

Burkitt lymphoma is similar to acute lymphoblastic leukemia (ALL) in that you have to incorporate prophylaxis against CNS involvement, even if the patient does not have evidence of CNS involvement at the time of initial presentation. For the systemic therapies that we use for most lymphomas, most of our drugs do not get into the CNS at meaningful concentrations to be able to address any occult disease or known diseases there.

The systemic therapies that have historically been used to [get into the CNS] are high doses of intravenous methotrexate, cytarabine, and ifosfamide. Those are all standard chemotherapy regimens that happen to have penetration into the CNS.

The EPOCH regimen that we're using has some penetration with a systemic therapy; etoposide phosphate has some penetration, but probably not to the same degrees that we're seeing with the other drugs. That was always a concern with using EPOCH in Burkitt lymphoma. Are we going to be addressing the CNS effectively? To overcome that limitation, they have added more intrathecal chemotherapy along with the systemic therapy to try to prevent CNS relapses. In real-world experience, it doesn't look like we were doing as good of a job as we were seeing in the trials.

How do you sequence therapies for Burkitt lymphoma?

With just EPOCH, it's a very active regimen in Burkitt lymphoma, although it might not be the first go-to regimen for somebody who has high risk of CNS disease. Perhaps you would consider using it in patients who had higher risk of complications from the more intensive chemotherapy regimens that include drugs with CNS penetration. They are a bit harder on the system; they have more neutropenic and/or neurologic complications with the more intensive regimen. It's not like there isn't a place for EPOCH; we just have to consider the patient population that might be best served by using it.

What area of research needs further investigation?

A lot of promising activity is seen with immunotherapy in general, including antibody-drug conjugates, such as brentuximab vedotin, and bispecific antibodies that are targeting a target on the tumor cell as well as bringing the T cells next to the tumor cell to have T-cell directed killing of the lymphoma.

Then, you have CAR T-cell therapy. We are expanding the targets that we can use with CAR T-cell therapy. Generally, I see immunotherapies as being a very promising arena, but there's still a lot of area for progress with other targeted therapies as we start to understand more about the biology of tumors and, with genomic, start to see more patterns that will help us differentiate what we now know as one category of lymphoma into one or more different subcategories.

What are some challenges with CAR T-cell therapy in lymphomas?

After CAR T-cell therapy, lymphodepletion can occur, which can be problematic from the standpoint of being able to prevent infections—at least temporarily. There is definitely a general lymphodepletion that occurs with CAR T-cell therapy. The acute issues are the ones that are related to neurotoxicity and cytokine release syndrome; we are gaining expertise in how to minimize or prevent [these adverse events] without compromising the efficacy.