Real-World Tisagenlecleucel Data Match Trial Results in Patients With ALL and DLBCL

In an interview with&nbsp;<em>Targeted Oncology</em>, Marcelo C. Pasquini, MD, discussed the importance of obtaining real-world data and establishing registries for collecting patient outcomes, and how real-world data compare with data from pivotal trials. He also explained the challenges with accessibility to CAR T-cell therapies.

Marcelo C. Pasquini, MD

Tisagenlecleucel (Kymriah) data collected in a real-world registry was consistent with outcomes of patients with acute lymphocytic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), seen in the ELIANA and JULIET trials, according to a presentation at the 2019 SOHO Annual Meeting.1

Of the 207 patients followed, 89% of the patients were in complete remission after infusion with the chimeric antigen receptor (CAR) T-cell therapy. Additionally, 82% tested negative for minimal residual disease.

Among patients who had been previously diagnosed with ALL, the 6-month leukemia-free rate was 66% and the overall survival rate was 89%. Treatment-related adverse events (TRAEs) occurred in 59% of these patients, with grade 3 and 4 cytokine release syndrome (13%) and neurotoxicities (8%) being the most prominent.

Patients with DLBCL had an overall response rate of 58%. Among them, 40% of patients had a complete response as their best response. As with patients with ALL, the DLBCL group had several occurrences of grade 3 and 4 cytokine release syndrome (43%) and neurotoxicities (16%).

Comparing these real-world data with clinical trial outcomes, patients in the ELIANA had a 90% overall response rate and a 73% event-free response rate.2Results from the JULIET trial were also consistent with these real-world data, as 40% of patients with DLBCL had a complete response.3

TRAEs occurred less frequently among real-world patients compared with trial patients. However, the TRAEs were consistent as far as grade level and type of toxicity.

All of these data show that real-word evidence collection can successfully capture patient outcomes after receiving CAR T-cell therapy for ALL or DLBCL. Real-world evidence is also important to the field because it can provide data from cases that are outside of the eligibility criteria of the clinical trial, thereby providing more information on how the treatment affects a wider population.

In an interview withTargeted Oncology, Marcelo C. Pasquini, MD, associate professor of medicine, Medical College of Wisconsin, discussed the importance of obtaining real-world data and establishing registries for collecting patient outcomes, and how real-world data compare with data from pivotal trials. He also explained the challenges with accessibility to CAR T-cell therapies.

TARGETED ONCOLOGY: Can you provide background on the real-world study of tisagenlecleucel CAR T-cell therapy in patients with ALL and DLBCL?

Pasquini:This study looks at a post-marketing assessment of tisagenlecleucel, which is an autologous CD19 CAR T cell. Tisagenlecleucel was approved 2 years ago for use in ALL and DLBCL. All of these CAR T cells are genetically modified cells and, as part of the approval process, the FDA mandated that the sponsors, or the industry, develop an infrastructure to follow these patients long-term. The concern is that these patients may develop second malignancies in the process of the manufacturing of these cells. The FDA mandated that these patients be followed for 15 years.

I work at the Center for International Blood and Marrow Transplant Research (CABMTR) and we have developed an infrastructure to capture follow-up of these patients who receive cellular therapies. A year ago, we started a prospective, observational study to look at the effect of this therapy in patients who have either ALL or DLBCL. Patients have been enrolled for less than a year. This study is the first look at how the real-word evidence is shaping up on the use of this product. We used the data from 207 patients and we presented the initial demographic information and also the initial efficacy and safety outcomes.

TARGETED ONCOLOGY: Can you comment on registry data as a whole and the value of registry data versus trial data?

Pasquini:CABMTR is an outcomes database. It relies on the voluntary reporting of data. We have been in existence for more than 40 years. We have a history of collecting real-world data and now it's something that everybody is talking about but the CABMTR have been doing this for a very long time in the transplant field. The transplant field is a data-driven field in part because of the availability of the registry. We understand more about outcomes.

The difference between the outcomes database and the clinical trial is that you have larger numbers. You have no prescription for how these patients are treated and how they are followed. They're followed as they would be in real practice. That's the big difference.

The application of that for cellular therapy is novel. When these cell therapies were approved, the efficacy looked outstanding, but there were some concerns with safety. I think having this assessment helped to have an understanding of what's going on with these patients when they receive that as a standard of care.

TARGETED ONCOLOGY: In comparing registry data with trial data, does either effect decision-making more than the other?

Pasquini:They are complementary to each other. With a trial, you control every single element of it, such as how often you assess and what you assess and also how long the trial will run for. Trials run for a short period of time, [they last] a few months to a few years. Very rarely will you see trials running for several years.

The registry complements trials. Oftentimes, what we do in the transplant world is we will have multicenter trials and patients enter the registry at the same time. When the trial is done, we continue following these trial patients to see what long-term effects occur in the patients who are enrolled in the trial. I think it is a supplement to the trial data collection.

TARGETED ONCOLOGY: How does this real-world evidence data compare with data from the ZUMA trials on axicabtagene ciloleucel presented at ASH 2018?

Pasquini:[Axicabtagene ciloleucel] is a different CD19 CAR T-cell therapy and it's mainly indicated for DLBCL. There's some overlap on the indications between axicabtagene ciloleucel and tisagenlecleucel for DLBCL. In that publication, they were able [to use] data from the real-world, which was from a combination of centers, not as wide as a registry would be. For example, in a registry we have over 80 centers contributing data. In that real-world evidence for axicabtagene ciloleucel, it was a limited number. But, I think the important aspect of that is the outcomes of safety and efficacy were very similar to the pivotal trials. That was always a concern because, with pivotal trials, you control who enters the trial, as you go to a commercial setting. Then patients who would otherwise be ineligible can participate. I believe there was a large proportion of patients who would have otherwise been ineligible who did participate in that study. That was an important study.

In the analysis for tisagenlecleucel that we presented at SOHO, we also noticed the same effect in the sense that we had patients who would not have been eligible for the trial. For example, in ALL, we had children younger than 3, [who did not meet the enrollment criteria for] the trial. The other element is that there were a higher proportion of patients older than 65 and a higher portion of patients with more aggressive B-cell malignancies than in the pivotal trial. For example, [there were more] double- and triple-hit lymphomas and transformed lymphomas. That has to be taken into account to assess the effect of this because now you have a population with much more aggressive disease.

In terms of the safety, we captured similar rates of [toxicities]. Although, one of the interesting aspects that we noticed with this analysis is that we have not seen as many cases of severe cytokine release syndrome and neurotoxicity as we've seen in the pivotal trials.

TARGETED ONCOLOGY: Some physicians have expressed concern that people will not report all of their data because there are no laws requiring them to. Do you see this being a problem?

Pasquini:Absolutely. Currently, the contribution to the registry is voluntary. The [existing] mandate is from the FDA to the companies for them to create a mechanism for collecting data. There are no mandates for the center or the patient, so that framework is still voluntary. This is important.

[With the registry], as we accumulate the data, we can keep these data in the public domain. If we didn't have a central location that was NCI or NIH funded, we would live in a world where each company would have a different registry, because the mandate is still there from the regulators to the company. [The mandate] is one incentive. So, we have to maximize the incentive for centers to report to the registry.

One way is to have a single place to collect all the commercial CAR T cells, which will give you a standard way of collecting the data rather than to multiple sources. A second way is to have the data in a public domain that can be used for proposals and secondary analyses and can be compared to further understand how to use these [therapies] so that there is a benefit. The third part is that we do reimburse for the data that are shared with the CAMBTR. Of course, we have to constantly be in tune to see if this is a fair market value for coverage. The fourth part is that registries are no longer like they were 10 or 15 years. Registries should be tools for centers to submit data and get value out of it. [This can happen when registries process the data in a way that they can be accessed easily by the original center(s).] That way, [the center of origin can pull their own data] or other centers can use the registry to obtain data, instead of investing in database development.

Moving forward, even if we don't have a mandate we [should] increase incentives for the collaboration of data, that would be a great approach and resource because the community would like to know more how to use these registries.

TARGETED ONCOLOGY: How do you see this research impacting the field as a whole?

Pasquini:If we learn from the transplant field, which is a very data-driven field, we learn a lot with that. The field was pushed forward by the availability of a registry. On the transplant side, multiple centers transplant few cases, so the power of the numbers with the registry helps. I think having a unique database with all commercial CAR T cells and also incentivized for noncommercial, preclinical use of these data would be a tremendous resource. We see this as a way that we can leverage the collection of additional data and integration with electronic medical record data, patient-reported outcome data, and devices that can communicate with a central portal. Then, investigators can access all of these data centralized in the registry. The vision for the future is thinking about a way to maximize this resource because if we think of this as a collaborative resource where everybody is working together, that is a great formula for advancing the field with these data.

TARGETED ONCOLOGY: What challenges exist with CAR T-cells?

Pasquini:CAR T-cell therapy is a specialized because of the associated [adverse] effects. The FDA recognized that pivotal trials came with a limited amount of patients and limited follow-up. When they approved these drugs, they specified a program called Risk Evaluation and Mitigation Strategy (REMS). This is a comprehensive program that requires you to choose appropriate centers to treat patients in, train the individuals that are caring for the patients, and have an assessment of how the toxicities are being managed.

With the REMS, it limited the accessibility to centers of excellence. Now, they've started with centers that have a transplant program. As these CAR T cells become less and less toxic, I predict that more centers can be involved with it.

I can see on the websites of both Kite Pharma and Novartis that the number of centers is increasing quite a bit. I think the accessibility, at least in the United States, is not an issue. Of course, there are other issues with it. The cost is a big issue. That's something that as many more CAR T cells become available and manufacturing complexities decrease, maybe the price will decrease and improve access.

The registry should not be viewed as a barrier to access because we're able to work with any center, whether it's a transplant center or not. There are certain requirements for the centers to be up and running. Patients are able to sign consent and authorize the data. That should not be an access barrier and we're trying to work as much as possible to alleviate any perceived barriers with reporting to the registry.

TARGETED ONCOLOGY: What is your key takeaway for physicians?

Pasquini:It's important to know that the resources are there and that this is not a tisagenlecleucel- or axicabtagene ciloleucel-specific registry. This is something that we are investing in to have a resource for all of us to understand how to better use these products in the future. CAR T cells are coming with a lot of challenges. The cost is very high and only centers that are specialized can treat [patients with ALL or DLBCL].

We have to find ways to make [CAR T-cell therapy] accessible to everybody and understanding the data and how to use the registry is the first step towards that.


  1. Pasquini M, Huan Hu Z, Zhang Y, et al. Real World Experience of Tisagenlecleucel Chimeric Antigen Receptor (CAR) T-Cells Targeting CD19 in Patients with Acute Lymphoblastic Leukemia (ALL) and Diffuse Large B-Cell Lymphoma (DLBCL) Using the Center for International Blood and Marrow Transplant Research (CIBMTR) Cellular Therapy (CT) Registry.Clin Lymphoma Myeloma Leuk. 2019;19(suppl 1):S267. doi: 10.1016/j.clml.2019.07.190.
  2. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia.N Engl J Med. 2018;378:439-448. doi: 10.1056/NEJMoa1709866.
  3. Schuster SJ, Bishop MR, Tam CS. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma.N Engl J Med. 2019;380:45-56. doi: 10.1056/NEJMoa1804980.