Lead Researcher Highlights Tisagenlecleucel Benefit in Younger Leukemia Patients

Stephan Grupp, MD, PhD

The CD19-targeted CAR T-cell therapy, tisagenlecleucel (Kymriah) demonstrated durable remissions in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to an updated analysis of the phase II ELIANA trial presented by Stephen Grupp, MD, PhD, at the 2018 ASH Annual Meeting.

Initial data from the trial showed a complete remission or complete remission with incomplete blood count recovery rate of 82% at 3 months. The updated data presented at ASH showed that the 24-month relapse-free survival (RFS) rate with tisagenlecleucel was 62% (95% CI, 47%-75%). At months 12 and 18, the RFS rate was 66% (95% CI, 52%-77%). Additionally, the 12-month overall survival (OS) rate was 76% (95% CI, 65%-85%) with tisagenlecleucel and the 18-month rate was 70% (95% CI, 58%-79%).

“The principal significance [of these findings] is that we can completely control refractory leukemia with this therapy a large fraction of the time—more than 80% of the time,” said Grupp. “What makes this much more transformative is that we can give this single therapy infusion over the course of several minutes with a push of a syringe knowing that it has the potential to be the last therapy this patient will ever need.”

In addition to the follow-up data, Grupp reported the relationship between duration of response and OS with minimal residual disease (MRD) status. In patients with a complete response, the likelihood of a durable response was 80% in the MRD-negative arm and 20% in the MRD-positive arm. No new safety signals were reported.

“The most exciting part of this is that we can achieve long-term disease control with the hope that these patients might be cured,” added Grupp.

The FDA approved tisagenlecleucel in August 2017 for the treatment of patients up to age 25 with B-cell precursor ALL that is refractory or in second or later relapse.

OncLive: Please provide some background on the ELIANA trial.

How was the study designed and what were the initial results?

In an interview with OncLive during the 2018 ASH Annual Meeting, Grupp, the director of translational research for the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia (CHOP) and medical director of the Stem Cell Laboratory at CHOP, discussed the updated analysis of the ELIANA trial and its implications for pediatric and young adult patients with relapsed/refractory ALL.Grupp: At the 2018 ASH Annual Meeting, we reported updated data from the ELIANA trial. ELIANA was the first registration trial with regard to CAR T-cell therapy. [The therapy] was tested in children and young adults with relapsed/refractory ALL. It’s exciting that we were able to do this in kids first. It was the first international study with the global supply chain. There were a lot of firsts in terms of understanding how the therapy works [in this population].The study was intended to evaluate how tisagenlecleucel performed in kids and young adults with relapsed/refractory ALL. Patients had to have a high disease burden. On average, they had about a 75% blast in their bone marrow when they were enrolled on the trial. The first goal [of the trial] was to see how many patients would go into remission—that was the primary endpoint—and about 82% of patients [were able to do that]. Those data have been consistent throughout the study.

Are there plans to bring the therapy into earlier lines of treatment?

Now that we have an update, we're able to say how the therapy performs long-term. We're seeing that in the 82% of patients in remission, approximately 66% are in remission at 12 and 18 months, while 62% [are in remission] at 24 months. Our median follow-up now is 24 months. That's starting to be a significant amount of time. It’s important to see that these patients are remaining in remission without needing bone marrow transplants. Only a small number of patients went to transplant.One of the more interesting questions is when the appropriate time to deploy this therapy is. In the 5 or 6 years that we've been doing this, we see that referring doctors are calling us earlier and not waiting as long [to reach out]. These patients have lower disease burden. It's much safer to do the therapy when you have less leukemia, although we can still administer the therapy safely [in patients with] very high amounts of leukemia as well.

Is there anything else you would like to highlight?

The Children's Oncology Group is beginning an international study to explore whether CAR T-cell therapy can be used as a frontline therapy in patients with leukemia who have not relapsed—specifically, in high-risk patients who still have MRD after receiving 2 cycles of chemotherapy to try to prevent the need for transplant. That trial is going to launch within the next month or two and it will be sponsored by Novartis. People are really excited about this trial.In the trial, we tested for MRD using the standard approach [used in the United States], which is a multiparameter flow. Almost all of the patients were MRD negative; only 1 was MRD positive. That’s great news, but it also means that there is no discrimination. Therefore, you don't have a positive and negative group to compare.

We resent those samples with something that's up to 100 times more sensitive. It’s a next- generation sequencing version of MRD done on DNA analysis, where they sequence antigen receptor gene rearrangements. Instead of being sensitive to the level of 10-4, it's sensitive up to the level of 10-6. Although there are limitations with a retrospective analysis, it revealed that 80% of patients who were MRD negative made it to remission, and 20% of those who were MRD positive made it to remission. For the 80% of patients, you could say that may be a group that doesn't require any further therapy. We’ll have to see. For the 20% of patients, we’ll have to do something else. Perhaps those patients need to go to transplant or maybe they will need another cell therapy treatment. We'll have to figure that out.

Grupp SA, Maude SL, Rives S, et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia. In: Proceedings from the the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 895.