CAR-T Leads Advances Across Lymphomas, But Further Research Needed

Dimitrios Tzachanis, MD, PhD

CAR T-cell therapy has emerged as a novel therapeutic approach to treat select patients with non-Hodgkin lymphoma, explained Dimitrios Tzachanis, MD, PhD.

“CAR T cells are here to stay,” Tzachanis said. “We now know that the technology works, and we hope that it is going to cure a large proportion of patients.”

However, he added, questions still remain on the differences between the available products, the optimal next steps for patients who progress on CAR T-cell therapy, and whether the clinical activity observed with this treatment will translate to cures.

Tisagenlecleucel (Kymriah), for example, is indicated for the treatment of patients with large B-cell lymphoma (LBCL)—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after ≥2 lines of systemic therapy. Secondly, axicabtagene ciloleucel (axi-cel; Yescarta) is approved as a treatment for adults with relapsed/refractory non-Hodgkin lymphoma.

Most recently, in February 2020, the FDA granted a priority review designation to a biologics license application for the anti-CD19 CAR T-cell therapy lisocabtagene maraleucel (liso-cel) for the treatment of adult patients with relapsed/refractory LBCL after ≥2 prior therapies.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Tzachanis, assistant professor of medicine at hematologist/medical oncologist at the University of California, San Diego, discussed updates and remaining questions with CAR T-cell therapy.

OncLive: Could you discuss the most recent advances with CAR T-cell therapy in lymphoma?

Tzachanis: In the lymphoma space, there was an update pertaining to 3-year follow-up data of patients were treated with axi-cel. We saw a flattening of the curve with [this CAR T-cell therapy] in remission after longer follow-up. The toxicity with this treatment is mainly seen within the first 8 weeks [of treatment] and the B-cell aplasia, the target, persisted for up to 2 years.

The presentation and data on [the ZUMA-2 trial] looked remarkable. KTX-X19 [was shown to be] effective in relapsed/refractory mantle cell lymphoma. I expect the drug to be approved for clinical practice soon.

What differentiates liso-cel from axi-cel and tisagenlecleucel?

The data show that liso-cel appears to be effective with [responses] around the 50% range. It can also cause cytokine release syndrome (CRS) and neurotoxicity, similar to [axi-cel and tisagenlecleucel]. [These agents] have never been compared side by side, making it hard to draw any conclusions about which product might be more effective or toxic.

There are fewer production problems with axi-cel as well, so when we might be worried about the availability of a CAR T-cell product, we might prescribe axi-cel.

Are there any research efforts on bringing these products into earlier lines of therapy?

We have the ZUMA-7 trial, which compares axi-cel with [chemotherapy followed by] autologous stem cell transplant in patients with relapsed/refractory lymphoma. This study has completed accrual and I hope that the data from that study will be presented at the 2021 ASH Annual Meeting.

Could CAR T-cell therapy eventually replace autologous stem cell transplant?

It could potentially replace transplant for patients whose chemotherapy does not work well for them. Transplants are not going to go away because they still have value.

Are there any research efforts focused on disease progression following CAR T-cell therapy?

There is a lot of research being done [in that area]. I have not seen much data reported, but we know for sure that patients who progress after CAR T-cell therapy do not do well. There are reports of agents that work in some patients. For example, at the 2019 ASH Annual Meeting we saw that CD20 bispecific T-cell engagers [are effective in] patients who relapsed after CAR T-cell therapy. The data are not [fully] there yet.

I would like to add that allogeneic transplant also has a role in those patients. It is important to think about transplant early enough, because it only works when a disease is under good control.

What else regarding CAR T-cell therapy would you like to emphasize?

As we become more experienced with the administration of CAR T-cell therapy and the management of associated adverse events, we can start to define our practice and fill in gaps that existed 1 to 2 years ago. Along those lines, the American Society for Transplantation and Cellular Therapy has recently made an effort on publishing guidelines to help with the grading and treatment of neurotoxicity, as well as supportive treatment of these patients. Publications on CAR T-cell therapy have become popularized over the last few years, and they will help us unify our practice.

Physicians need to keep [patients who are eligible for] CAR T-cell therapy in mind. We now know that older patients with CRS who used to be excluded from CAR T-cell treatment can also be successfully treated.

There needs to be a greater effort to educate physicians on [how to best] refer patients for CAR T-cell therapy, because a significant proportion of patients who were thought to be incurable just a couple of years ago can now be cured with [this type of treatment].

What will longer follow-up with CAR T-cell therapy inform?

The only time we will know for sure that there is a cure is when these patients die from something else [other than their cancer]. Unfortunately, I do not think there is a set time point that we can say that patients are cured.

However, taking into account the kinetics of this disease—because both DLBCL and acute lymphocytic leukemia are fast going diseases—we hope that these 2-year remissions [with CAR T-cell therapy] will translate into cures.

References

1. Wang ML, Munoz J, Goy A, et al. KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients (Pts) With Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL): Results of the Phase 2 ZUMA-2 Study. Presented at: 2019 ASH Annual Meeting, Orlando, FL, December 7-10, 2019. Abstract 754.
2. Oluwole OO, Bishop MR, Gisselbrecht C, et al. ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard-of-care (SOC) therapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). J Clin Oncol. 2018;36(suppl 15; abstr TPS7585). doi: 10.1200/JCO.2018.36.15_suppl.TPS7585.