Targeted Approaches Under Exploration in Peripheral T-Cell Lymphoma

Aaron Goodman, MD

To move the needle forward in peripheral T-cell lymphoma (PTCL), research efforts should be focused on specific disease subtypes, according to Aaron Goodman, MD, a hematologist and medical oncologist at the University of California, San Diego (UCSD) Health.

“We need to focus on specific populations. We're learning more about the genetics of these diseases every day, so my hope is we’ll get to the same place in T-cell lymphomas as we did with acute myeloid leukemia, which is comprised of many different molecular subtypes,” said Goodman.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Goodman, who is also an assistant professor of medicine at UCSD Health, discussed recent changes to the frontline treatment of patients with PTCL and the challenges of targeting T-cell lymphoma.

OncLive: Would you attribute the lack of progress in PTCL to the rarity of the disease?

Goodman: Numerous factors contribute to the lack of progress [in PTCL]. Yes, one factor is the rarity of PTCL, which, according to various registries, accounts for 10% to 20% of all cases of non-Hodgkin lymphoma. The other problem is that this is a very heterogeneous disease. The more we learn about PTCL, the more subtypes we come up with. Unfortunately, each disease is responsive to slightly different agents. Finally, unlike B-cell lymphomas where we can target CD20 and [BTK], [there was no good target in] PTCL until recently.

Could you discuss the importance of the ECHELON-2 trial?

This is the first multi-institutional, randomized study that showed a progression-free survival and overall survival (OS) benefit in those with PTCL, which is a very challenging population to treat. The population in the study was predominantly patients with anaplastic large cell lymphoma (ALCL), but it also included some of the more difficult-to-treat PTCLs, including angioimmunoblastic T-cell lymphomas.

The addition of brentuximab vedotin (Adcetris) to chemotherapy resulted in the first OS benefit [we’ve seen in a randomized setting in PTCL]. For the first time since I’ve been practicing, the frontline treatment for [patients with] CD30-expressing PTCLs changed. [Brentuximab vedotin plus chemotherapy] is in the guidelines [for frontline treatment of patients with PTCL], and I believe it should be universally adopted.

What is the role of transplant in T-cell lymphoma?

The role of autologous stem cell transplant (ASCT) in PTCL is controversial. The controversy arises in patients who achieve first complete remission (CR1) after CHOP or brentuximab vedotin plus CHP. Should these patients receive high-dose chemotherapy with ASCT? Numerous studies are looking into this, but we don’t have randomized data [available to adequately] address this question; as such, we don’t have a definitive answer. I believe it depends on where the patient is referred to and who is seeing them.

Most phase II studies and retrospective studies show better outcomes with ASCT in [patients in] CR1 compared with controls who did not receive ASCT. However, there are many problems with these data because [they are] biased. Patients who can get a transplant are more fit and are going to do better. When you're analyzing the literature of ASCT in patients with T-cell lymphoma in CR1, it's all about the population of patients enrolled. Those with ALCL whose tumors are ALK positive do really well. In some of the earlier transplant studies, those patients were included. It’s now universally accepted that we should transplant ALK-positive patients in CR1.

[Whether we should recommend transplant] is an evolving question that’s becoming more complex. We see better outcomes in patients who achieve a CR1 after receiving brentuximab vedotin plus CHP, but do we still need transplant? Investigators looked at a subset of patients who underwent transplant after achieving CR1 with brentuximab vedotin in the ECHELON-2 trial. Those patients did extremely well, with a PFS ranging from 70% to 80%, which is unheard of. However, these data came from a subset of a subset that's extremely susceptible to biases, so I don't believe we know the answer. My practice has generally been to discuss the pros and cons [of transplant] and take it on a case-by-case basis with the patient.

What is the best way to approach clinical trials in PTCL?

We’re going to have to keep PTCLs separate from other lymphomas because they are such different diseases. Ideally, we would have trials for more specific populations. The angioimmunoblastic population, which is a subset of an already rare disease, appears to be more responsive to hypomethylating agents and histone deacetylase inhibitors.

Are there any other potential targets that are under investigation in PTCL?

There have been some data with PD-1 inhibitors. Initially, there was a lot enthusiasm [for this approach], but [PD-1 inhibitors] haven’t panned out so well; response rates have ranged anywhere from 10% to 30%. With T-cell lymphomas, unlike other cancers, we're targeting a protein on the tumor that can activate the tumor; we’re releasing a natural break on the tumor cells. There have been reports of hyperprogression in T-cell lymphomas treated with pembrolizumab (Keytruda) and nivolumab (Opdivo), so we need to practice caution with those agents. As far as other targets, a newer drug has been approved for use in cutaneous T-cell lymphomas called mogamulizumab-kpkc (Poteligeo). Mogamulizumab-kpkc is a monoclonal antibody that targets CCR4, which is found on regulatory T cells and malignant T cells, specifically in mycosis fungoides or Sézary syndrome. [The agent] has reasonable activity as a monotherapy that can be durable in that population.

Could you discuss the preclinical research being done with CAR T-cell therapy in T-cell lymphoma?

We have early phase I [data] and a lot of preclinical data [with this approach]. There's something called fratricide, in which the CAR T cells will kill themselves if you target a T-cell antigen, unlike CAR T cells in B-cell malignancies. Patients with [B-cell malignancies] can do well without B cells for a period of time. You can give [patients] immunoglobulin replacement. Patients can tolerate B-cell aplasia, which is a known complication of the approved CD19-directed CAR T-cell [products].

Patients cannot do well without T cells. If you target CD3, CD4, or CD8, you will lose cellular-mediated immunity and patients will die from infections. The question is how to get around those major limitations. There is some early work looking at tumor-specific antigens for various T-cell malignancies, including CD30; however, that [target is] not universally expressed on all T-cell lymphomas.