Part 1: Kline Discusses Challenges of CAR T-Cell Therapy in R/R DLBCL

Justin Kline, MD​

Associate Professor of Medicine​

Director, Lymphoma Program​

University of Chicago Medicine​

Chicago, IL​

During a live virtual event with other physicians, Justin Kline, MD, discussed the role of CAR (chimeric antigen receptor) T-cell therapy in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) and the challenges clinicians face with this treatment in this patient population. Kline also looked at the most noteworthy adverse events (AEs) that patients should expect from CAR T-cell therapy.

What data have led to the approval of axicabragene cilolucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), and lisocabtagene maraleucel (liso-cel; Breyanzi) for patients with R/R DLBCL?

KLINE: All of the studies have shown a fairly impressive overall response rate (ORR), as high as 83% in the ZUMA-1 trial (NCT02348216), which was the first study that was published and the first that led to the approval of axi-cel.¹ The long-term complete response rates were also roughly similar, and you’re looking at about 30% to 40% of the patients that seemed to have achieved a durable complete response.

The studies have also indicated that for patients who are in complete response at 6 months, and certainly at 12 months, the likelihood of relapse after that period is relatively low. However, for the patients who achieve no response, or a partial response, their outcomes are quite poor.

Median survival is on the order of a couple months, so once patients have a failure or early progression after CAR T-cell therapy, their disease is very difficult to salvage. Very few survive more than a few months unfortunately. At least in academic centers, it is becoming 1 of the biggest areas of unmet need, and R/R DLBCL is basically “What do we do with patients who fail CAR T-cell therapy,” because there are plenty of them.

Is there a specific reason why these treatments are difficult to salvage post CAR T-cell therapy?

I separate the relapses into early relapses or failure, and later relapses. So, the early relapses are basically patients that never really responded or had a very brief, fleeting response. Their bodies are also beat up from the CAR T-cell therapy to begin with.

They also often have cytopenias, which are a common problem that we see even in patients who do well after CAR T-cell therapies. It’s hard to deliver additional cytotoxic chemotherapy for those reasons, and a for a patient with DLBCL that fails to respond to CAR T-cell therapy, it is a tough choice, and they’re probably not going to respond to anything else.

For the smaller group of patients who relapse late after CAR T-cell therapy, they seem to fare a little bit better. They’ve had a little more time to recuperate, as has their bone marrow, and I think these folks are more likely to tolerate and respond to subsequent therapies. A small subset of patients, especially the younger ones, will go on to allogeneic transplant, which occasionally can be successful. Their outcomes are still poor, but not nearly as poor as patients who fail early [on the treatment].

Is there a role for T-lymphocyte infusions for this patient population?

For most of the patients on [studies investigating these CAR T treatments, most] had never received transplant before, so there’s no donor lymphocytes that are available to infuse.² For patients who relapsed late after their initial CAR T infusion, they tend to respond to a second CAR T-cell infusion. For patients who fail early, it doesn’t make a lot of sense to treat them again with CAR T-cells. However, outside of the clinical trial, it’s very difficult to gain approval from an insurance company to do that given the expense.

What toxicities should clinicians look out for with CAR T-cell therapy?

The acute toxicities of CAR T-cell therapy are important for community oncologists to be aware of, although these aren’t things they’ll be dealing with once the patient comes back into their care. From our perspective, there’s a significant difference in the rates of key toxicities [patients will experience].³ For example, cytokine release syndrome (CRS) and neurotoxicity known as immune effector cell-associated neurotoxicity syndrome [should be looked out for].

The axi-cel investigators observed about 10% to 15% of patients develop grade 3 or grade 4 CRS, [which led to] intensive care unit stays. About one-third of patients developed severe neurotoxicity, and the high-grade CRS is a little bit more common with tisa-cel.

Although, the neurotoxicity seems to be lower with liso-cel, which is the most recent CAR T-cell product approved.⁴ But still, these are important AEs that can be, in some cases, life-threatening. I will say that in the past 3 years, we’ve become better at recognizing and mitigating these problems earlier with antidotes like anti–interleukin-6 therapies and corticosteroids.

What are the guidelines from the National Comprehensive Cancer Network in this patient population to address toxicities?

What’s important for community oncologists to be aware of is that patients that receive CAR T-cell therapy often develop delayed cytopenias that can require intermittent filgtastim (Nubigen) or granulocyte-colony stimulating factor support.⁵ Occasionally transfusions of platelets or red blood cells [are recommended], and these can persist for weeks, or sometimes even months, after CAR T-cell therapy but the mechanism is a little bit unclear.

Patients also receive feudality and incyclofocimide conditioning before their CAR T infusion, and the cytopenias may be at least in part because of the chemotherapy. But there also seems to be cytopenias that are probably related to cytokines produced either by the CAR T cells or indigenous immune cells, and so, this is an issue that can lead to delayed infections after CAR T-cell therapy.

The second major issue is the low antibody levels, or hypogammaglobulinemia, and in some cases [patients have] B-cell aplasia. I know it’s typical to administer it intravenously unless there are infections complications, but this is an issue in some patients, particularly when they come back to see [their medial care team].

_References

_{1. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7}

_{2. Liu J, Zhong JF, Zhang X, Zhang C. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies. J Hematol Oncol. 2017 Jan 31;10(1):35. doi: 10.1186/s13045-017-0405-3}

_{3. Locke FL, Neelapu SS, Bartlett NL, et al. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma. Mol Ther. 2017 Jan 4;25(1):285-295. doi: 10.1016/j.ymthe.2016.10.020}

_{4. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. News release. February 5, 2021. Accessed November 8, 2021. https://bit.ly/3H2Sqi1}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Diffuse Large B-Cell Lymphoma; version 4.2020). Accessed November 8, 2021. https://bit.ly/3EYNRTL}