Lead Investigator Says Tisagenlecleucel Has Changed Natural History of DLBCL

Richard T. Maziarz, MD

At more than 1.5 years, over 50% of patients with diffuse large B-cell lymphoma (DLBCL) demonstrated a sustained and significant clinical response to tisagenlecleucel (Kymriah), highlighting the long-term efficacy of this type of therapy, according to Richard T. Maziarz, MD.

Updated data from the JULIET trial, which were presented at the 2018 ASH Annual Meeting, showed that at a median follow-up of 19 months, the overall response rate (ORR) was 54% (95% CI, 41%-62%) with the CD19-targeted chimeric antigen receptor (CAR) T-cell therapy. There was a complete remission (CR) rate of 40%, with the remainder of patients achieving a partial response.

“I would say that with this therapy, the natural history of lymphoma has just changed,” said Maziarz, lead author of the study.

The preliminary JULIET findings were the basis for the May 2018 approval of tisagenlecleucel for use in adult patients with relapsed/refractory large B-cell lymphoma—including DLBCL, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after ≥2 lines of systemic therapy.

In JULIET, eligible patients were ≥18 years with relapsed/refractory DLBCL, had received ≥2 lines of therapy, including rituximab (Rituxan) and an anthracycline-based regimen, and were ineligible for or had failed stem cell transplant. At the data cutoff in May 2018, 115 patients were infused with a single median dose of tisagenlecleucel 3.0 × 108 (range, 0.1-6.0 × 10⁸).

OncLive: Please provide some background to the JULIET study.

In an interview with OncLive during the 2018 ASH Annual Meeting, Maziarz, a professor of medicine at Oregon Health & Science University, Knight Cancer Institute, discussed the updated findings from JULIET and their clinical implications for patients with DLBCL.Maziarz: This is the study that led to the FDA approval of tisagenlecleucel, which is the CAR T-cell product used against the CD19 target molecule in patients with relapsed/refractory lymphomas. This is a disease with a myriad of subtypes, and there are about 75,000 cases per year in the United States. About one-third of those patients have DLBCL. It has an aggressive behavior, but about 60% of them can be cured with chemotherapy and immunotherapy. The other 40% cannot be cured.

Therefore, we move on from chemotherapy to transplant to try to control the disease, but that is only if you can get the patient into remission. A lot of these patients do not make it there or they relapse after transplant. If we look at the outcome of those patients at that time, it is actually very, very poor. Whenever there has been both retrospective and prospective studies, if you try to implement a therapy in that really high-risk setting, there is probably only about a 7% ability to achieve remission, meaning approximately 93% of patients will die from their disease. Only about 20% of patients are alive after 2 years.

The patients’ own immune cells have become tolerant to the cancer; they have let the cancer escape from their watch. Therefore, we take the T cells out of the patient's body and genetically alter them. It is a construct that will then force those immune cells to have a new receptor. The beauty of this is that the immune cells live in your body for life. [The vaccines one receives] as a child are an example—you have immunity for lifetime. The cells can functionally live. Therefore, we take these T cells that may initially have a receptor that is irrelevant to the disease and make them now focus on the cancer. When you put them in, you immediately get an immune response to the residual cancer in the body.

What findings are being presented at the 2018 ASH Annual Meeting?

We will see a massive number of cells that will grow. The beauty of it is that it works. A lot of people were surprised to see the biology we actually predicted and the fact that it works in humans and not just mice.We are now seeing long-term responses. The importance of that is sometimes you will present initial data, and people will say, "Well, maybe we are seeing these results because of this or that. Maybe it had something to do with the selection, the patients, or the design.” In the JULIET trial, we are now over 1.5 years out from the time of infusion.

What is it about the mechanism of action of this drug that makes it unique?

What is the biggest takeaway with these updated data?

What unanswered questions remain with CAR T cells?

There is a median follow-up of 19 months. What we are seeing is that over 40% of patients are in remission and have sustained remission, and 54% of the patients have either CR or partial remission. Over time, these patients can still go into remission; the cells continue to work over time. These patients otherwise face a very poor prognosis, and in a lot of cases we are asking ourselves, "How do we prepare them to succumb to their disease? How do we make them most comfortable?" That is what palliative care is. Now, we have the ability to give these patients new life.It is probably a combination of the design and of the product of itself; the new construct of the gene that is put in is well-designed. They activate the T cells effectively and drive that cell product to persist in the individual. Part of the genetic construct of tisagenlecleucel favors persistence in the individual.The biggest takeaway is that 54% of patients had a significant clinical response to this treatment. One of the most important messages is that when patients get into remission, they stay in remission. When you look at the likelihood of them falling out of remission, it is very rare, although we obviously do not have data that are years down the line. It is a sustained response. We are seeing similar results with the other CAR T-cell products.First and foremost, we put the patient at the center of our attention. We can say in the past that we expected 15% to 20% of patients to be alive; now, we expect 40% to be alive at the 2-year point. The nature of the disease is that if you are alive at 2 years, you're going to go the distance. We have to understand why the disease still grows, and there are ways we can enhance this product even more to increase our success rate.

There is a series of side effects that come with this treatment. In order for cells to grow very fast, sometimes there is a proliferation event and that comes with its own set of negative effects. We need to improve the safety of this product so we can give it to all patients.

There are a number of other trials ongoing of other CAR T products. The nature of the trials is twofold. First, what can we do to better understand the means as to why patients are not getting into CR? Is there something we can add in [early on] to increase likelihood of success? Next, these are therapies being offered to very advanced patients. Once you can show benefit and a safety profile, why not use it earlier?

Schuster SJ, Bishop MR, Tam C, et al. Sustained disease control for adult patients with relapsed or refractory diffuse large B-cell lymphoma: an updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018. San Diego, CA. Abstract 1684.