Tisagenlecleucel Durability Data Generate Excitement in DLBCL

Long-term follow-up data from the phase II JULIET study are providing hope that the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) could represent a cure for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to Peter Borchmann MD.

“Obviously, it's a bit early still. We should wait another 6 months to 1 year to know for sure how many patients will remain in remission for, hopefully, a really long time,” he said. “Then, we can talk about cure. It's a bit too early now, but the data are still looking good, so this is why all of us are very motivated to proceed with tisagenlecleucel.”

Borchmann, a professor in the Department of Internal Medicine, University Hospital of Cologne in Cologne, Germany, presented updated results from JULIET at the 2018 European Hematology Association Congress. The findings included an additional 8 months of follow-up since results were last presented at the 2017 ASH Annual Meeting.

At a median follow-up of 14.1 months, the objective response rate (ORR) was 52% (95% CI, 41-62) in adults with relapsed/refractory DLBCL. The complete response (CR) rate was 40% with a partial response (PR) rate of 12%. The duration of response had not been reached.

The median overall survival (OS) among all infused patients was 11.7 months (95% CI, 6.6-NE), with a 12-month OS rate of 49%. Median OS was not reached for patients in CR (95% CI, 17.9-NE), and the 12-month OS rate was 95% for these patients.

The response status at 3 months indicated durable clinical benefit; the estimated progression-free survival (PFS) rate at 12 months was 83% for patients with CR or PR at 3 months.

In April 2018, the FDA approved tisagenlecleucel for adults with relapsed/refractory DLBCL, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma following ≥2 lines of systemic therapy based on data from JULIET. In August 2017, Tisagenlecleucel became the first CAR T-cell therapy approved by the FDA when the agency authorized the treatment’s use for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.

OncLive: Can you discuss the study’s design and the results?

In an interview with OncLive^®, Borchmann shed light on the updated JULIET data and how tisagenlecleucel fits into the paradigm of DLBCL.Borchmann: JULIET is a very important trial in patients with relapsed/refractory DLBCL failing at least 2 prior lines of systemic therapies. In this patient population, we have a very high unmet medical need. The OS in this patient cohort is short, with a median OS of approximately 4 months.

The primary endpoint of the phase II study was best ORR and has been reported previously. Based on these results—the high response rates in the phase II study—tisagenlecleucel has already been approved by the FDA.

The design was quite straightforward. We're treating adult patients with confirmed DLBCL, either de novo or transformed from follicular lymphoma. They had to have received at least 2 prior systemic therapies.

Bridging chemotherapy was allowed in this trial. The fact that so many patients in this cohort received bridging chemotherapy just reflects the very aggressive nature of the underlying disease of patients enrolled into this trial.

We now have an update with a median follow-up of 14 months. This is more meaningful follow-up for survival outcomes, like the duration of responses, the PFS, OS, and also for safety analysis.

What we have observed with this longer follow-up is very encouraging duration of responses. We see this plateau for patients achieving a CR over a longer period of time now, and, again, the number of patients achieving CR is high at 40%. When looking at the PFS in the entire cohort, including those who failed treatment, it's only 3 months. However, we see the plateau around 40% in this cohort as well, which is built upon the CR patients. We also observed that many patients convert from PR to CR over time and this can occur as much as 9 or 12 months later.

In all responding patients, we can follow the gene signature of the CAR T cell for up to 2 years, indicating that there is ongoing efficacy just from this single infusion.

Did you learn anything about safety with the longer follow-up?

We also have very encouraging survival curves. We have an OS at 12 months for the entire cohort of 49% and for the CR patients, it is 95%. The median OS for all patients, including those failing treatment, is 11.7 months, and, obviously, it has not been reached for the CR patients because of the plateau—it's way above 50% for these patients. This is good news for the patients.We had a closer look at safety signals in the study. There are some safety aspects of special interest in CAR T-cell therapy: cytokine release syndrome (CRS) and neurological events. We observed CRS in many patients; 58% of patients experienced some grade of CRS but only a few of them experienced grade 3 or greater at 22%. Fortunately, and importantly, none of them died due to CRS, so it could be managed.

The same is true for neurological events. The incidence is way lower; grade 3 or greater was [reported in] 12%. You could expect to see patients with cerebral edema dying from these events, but this has not been observed in the JULIET trial. Therefore, tisagenlecleucel seems to be really safe, and this is a large cohort of patients.

When looking into the details of CRS, we found the median time to onset of CRS to be 3 days and the median duration to be 7 days. We also found some predicting factors for developing any-grade CRS or neurological events: tumor burden or high lactate dehydrogenase, and the pre-infusion inflammatory status in the patient reflected by ferritin and C-reactive protein levels. If those are really high, this is predictive for the development of CRS or neurologic events.

Based on these results, what are your next steps?

In contrast, there is no significant relationship to the cell dose for CRS, neurological events, or efficacy, which could be expected.Looking at the very encouraging results with very long follow-up, we as physicians would like to see tisagenlecleucel in earlier lines of therapy. We are now in a really difficult situation—third, fourth-, or fifth-line aggressive B-cell lymphoma. This is a really difficult-to-treat patient population. We are looking at second-line treatment for transplant-ineligible patients or transplant-eligible patients; outcomes are not very good. They are way below 50%; they're around 20%.

Even for transplant-eligible, young patients, 3-year PFS is 20% in randomized trials. In the second-line setting, we not only could, we should improve to the best ORR for all patients. That's why a randomized phase III trial has been planned and will start, hopefully, sooner rather than later, comparing tisagenlecleucel with standard high-dose chemotherapy with autologous stem cell support. This will be a very important trial.

What is the take-home message from these results?

We use high-dose chemotherapy and stem cell transplantation; however, efficacy is not very good and toxicity is extremely high. If you compare this intervention with CAR T-cell therapy as we have seen with tisagenlecleucel in the JULIET trial, the risk-benefit ratio seems to be clearly better with CAR T-cell therapy. This old-fashioned, aggressive approach should be challenged.With longer follow-up, we still see this stable plateau for responding patients and at very high levels. Still, it's only 14 months; however, all of us hope we can cure patients in a desperate situation. Thus far, we don't have to revise this hope. With the data we have seen, we can say [the responses seem] very stable although they are 1 year out. With conventional treatments after 1 year, most patients will have relapsed and died already.

Borchmann P, Tam CS, Jager U, et al. An updated analysis of JULIET, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL). In: Proceedings from the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S799.