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Lead Investigator Says Tisagenlecleucel Has Changed Natural History of DLBCL

Brandon Scalea
Published: Wednesday, Jan 23, 2019

Richard T. Maziarz, MD

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).

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.

OncLive: Please provide some background to the JULIET study.

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.

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.

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

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.

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