CHOP-Based Combinations Represent Evolving Standard of Care in Frontline Treatment of PTCL

CHOP-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care in the frontline setting for patients with peripheral T-cell lymphoma (PTCL). Although the addition of agents including etoposide and brentuximab vedotin (Adcetris) to CHOP therapy have produced improved outcomes for certain subsets of patients with PTCL, more research is needed to reduce the risk of relapse in this population, according to Neha Mehta-Shah, MD, MSCI.

“Enrollment of patients to clinical trials is essential. These are rare diseases for which we’re only going to [provide better treatments] if patients can access clinical trials,” Mehta-Shah explained. “Look out for clinical trials for your patients both in the frontline and the relapsed/refractory settings. There are lots of drugs in development that have appeared to be far more promising and less toxic than the drugs that we currently have available for patients.”

In an interview with OncLive^® during the 2022 Pan Pacific Lymphoma Conference, Mehta-Shah, an associate professor of medicine in the Division of Medical Oncology at the Washington University School of Medicine in St. Louis, discussed her presentation on frontline therapies in PTCL, highlighting the current treatment landscape and the need to explore more treatment options in clinical trials.

OncLive^®: Could you expand on the need for clinical trials in PTCL?

Mehta-Shah: PTCLs represent a grab bag of different diseases, some of which are treated a little bit differently from others, but the majority [are treated] similarly. While there have been attempts for major advances in the field, some of those attempts have not worked out as well as we would have hoped, leaving a lot of room for improvement. There are clinical trials in progress to continue to advance the field in PTCL.

What is the current standard of care in the frontline setting for patients with PTCL? What factors go into making treatment decisions?

Most patients with PTCL fall into 1 of 4 general categories: PTCL not otherwise specified [NOS], anaplastic large cell lymphoma that then gets divided based on the presence of the ALK protein (ALK-positive and ALK-negative), and angioimmunoblastic T-cell lymphoma.

There are some variations in the nomenclature between those terms. But, in general, patients are treated with chemotherapy for 6 cycles. Usually, it is based on the chemotherapy regimen CHOP. Most of these patients are treated with an anthracycline, and in certain patients, we choose to add brentuximab vedotin [Adcetris] to CHOP-based therapy. That is the standard of care in anaplastic large cell lymphoma and is used often in other forms of PTCL.

For patients who are fit and responding well, we may sometimes consider an autologous stem cell transplant following the completion of treatment, which [is thought] to improve outcomes in a subset of patients. After that, we hope that patients will not have recurrence of their disease, and they’re treated for the purpose of cure.

What are some of the strategies that go into utilizing the CHOP regimen?

CHOP has been the standard of care for many lymphomas for many years. The way that we give CHOP chemotherapy has remained relatively standard. Patients are monitored for neuropathy, constipation, infections, and low blood counts throughout [treatment]. The bigger question is: When do we decide to deviate from giving CHOP alone to adding something to CHOP in certain patients? Some providers may opt to use etoposide with CHOP, and that’s a regimen called CHOEP, where you take etoposide chemotherapy for 3 days with each cycle of CHOP.

Similarly, some practitioners will opt to give brentuximab vedotin with CHOP, referred to as BV-CHP, [where we] reduce the vincristine. In anaplastic large cell lymphoma, there is a very clear improvement in progression-free survival [PFS] and overall survival [OS] with the addition of brentuximab vedotin–based therapy. This is predominantly because anaplastic large cell lymphoma universally expresses the protein CD30, which is the target of brentuximab vedotin, an antibody-drug conjugate against CD30.

Could you expand on what the phase 3 ECHELON-2 trial (NCT01777152) showed when comparing CHOP vs BV-CHP in patients with PTCL?

The ECHELON-2 study had included patients who did not have anaplastic large cell lymphoma. This represented about 30% of the patients on the study. When you looked at the study overall, there was an OS benefit [favoring BV-CHP in all patients]. There are providers who will opt to give patients who have CD30 expression [BV-CHP], even if they have PTCL NOS or angioimmunoblastic T-cell lymphoma, and that’s a standard approach.

The ECHELON-2 study led to the [FDA] approval of BV-CHP [as a treatment for] patients who have CD30-expressing PTCL.

When the investigators published the 5-year follow-up data on that study, we saw that the improvement seen was more in the patients who had anaplastic large cell lymphoma than any other subgroup, although the study was not powered to look for differences among subgroups. Some of us have taken that to mean that there may not be that much of a benefit to BV-CHP over CHOP. There are certainly some more adverse effects [AEs] with BV-CHP vs CHOP.

There are other ways of potentially augmenting therapy. One of the other approaches is to add etoposide to CHOP-based therapy in patients under the age of 60. This seems to also improve outcomes, [based on] pooled retrospective analyses of multiple prospective studies that were done by the German Non-Hodgkin Lymphoma Study group. [The group] pooled their analyses of patients with T-cell lymphoma treated with CHOEP, and they reported an improvement in outcomes. However, this has never been compared head-to-head [with the standard CHOP regimen].

In the United States, we are building upon this base of knowledge to study newer up-front therapies in PTCL for those who do not express CD30 at a high level. In the phase 2 A059102 trial [NCT04803201], patients are randomized to CHOP or CHOEP, based on their age. If patients are under the age of 60, they get CHOEP. If they’re over the age of 60, they get CHOP. Patients are either randomized to [their age-specified] chemotherapy alone, chemotherapy plus duvelisib [Copiktra], or chemotherapy plus oral azacitidine [Onureg].

Are there any other ongoing clinical trials that could affect the frontline treatment landscape in PTCL?

While there are not others in the United States, there are other studies that are have recently been presented, including a large phase 3 trial [NCT01796002], conducted by the Lymphoma Study Association, using romidepsin [Istodax] with CHOP-based therapy. This was unfortunately a negative study, [but data were recently reported].

As you can imagine, doing studies in PTCL requires large national studies, or even international studies, because these are rare diseases. Most centers only see a few patients per year, leading to the need for studies to be done across many sites in collaboration with doctors across the country with a common goal. The US Intergroup facilitates those types of studies and has allowed for that [large-scale research].

With the development of newer drugs for PTCL, there will be other up-front studies that are developed in the future, but few to my recollection are open right now. [However, Alex Herrera, MD, of City of Hope, led] a phase 2 trial [NCT03113500] that studied brentuximab vedotin with CHEP—basically giving brentuximab vedotin with CHEP—in this patient population. The initial results from this multi-institution, early phase study showed impressive results and high response rates. However, the follow-up presented in 2021 was still relatively short, so we’re looking forward to longer-term follow-up data, and there’s a plan to expand that study to a larger study.

What unmet needs still need to be addressed in future studies?

There are a lot, but to summarize [a couple key needs], most of our patients who have PTCL may suffer a relapse. With the current therapies, the 5-year PFS is somewhere in the 40%-50% range, which means there’s still a large share of patients who continue to suffer from PTCL and were not cured with their initial therapy. In these more common types of PTCL, being able to come up with tools to predict who’s going to respond is critical. If we know that a patient may not respond well to CHOP-based therapy, then we would want to switch them to something that might be more effective.

For patients who have relapsed disease, allogeneic stem cell transplants can be curative in up to 60% of patients. So, trying to get those patients to those sorts of therapies, if they are candidates for it, is important. That requires better drugs in PTCL. In the past 5-10 years, there’s been a major shift in trying to do studies specific to PTCL. Prior to that, there were very few drug developments specific to PTCL. Now, there is not only an interest amongst doctors, but also patients and patient advocates across the country, to put in energy and funding into studies of rare diseases, which has moved the needle.

Similarly, tools to look at other predictors of response, such as PET scan responses, continues to be an ongoing area of investigation. In the US Intergroup study, we will look at PET scans to figure out whether we can use that to determine who’s more likely to be cured partway through their treatment at an interim scan, and looking at blood markers, such as cell-free DNA, to see if those blood tools can help identify patients who are likely to respond or may be resistant to therapy. Similarly, in that study, we will look at the genomics of PTCL. There is a thought that patients who have PTCL that originates from the T follicular helper cell may be more sensitive to some of these therapies. Those [patients] often have some genes that are commonly mutated. Therefore, identifying whether there could be genes that you could test for at the start of treatment could help you predict which patients are more likely to respond to which therapy.

These are just a few [of the studies attempting to address the unmet needs in PTCL]. There are many more ongoing in the United States and across the world.