Tisagenlecleucel OS, RFS Sustained in Long-Term Follow-Up for Pediatric ALL

Stephan Grupp, MD, PhD

Treatment with the CD19-targeted CAR T-cell therapy tisagenlecleucel (Kymriah) demonstrated sustained rates of relapse-free survival (RFS) and overall survival (OS) at 24 and 18 months for pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL), according to updated findings from the phase II ELIANA study presented at the 2018 ASH Annual Meeting.

In the data, which included an additional 11 months of follow-up, the 24-month 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 OS rate was 76% (95% CI, 65%-85%) with tisagenlecleucel and the 18-month rate was 70% (95% CI, 58%-79%).

"This is an update to a registration trial. This was the first CAR T cell trial with a potential registration endpoint, the first global trial, and the first trial where there was a global supply chain," said lead investigator Stephan A. Grupp, MD, PhD, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania. "This has moved forward to approvals in the EU, Canada, and Switzerland."

At the data cutoff of April 13, 2018, there were 97 patients enrolled in the ELIANA trial, of which 79 received a single dose of tisagenlecleucel at a median dose of 3.0 x 10⁶ CAR-positive T cells per kilogram. The median age of patients in the trial was 11 years (range, 3-24) and 61% had received a prior stem cell transplant.

The rate of complete remission or complete remission with incomplete blood count recovery at 3 months was 82% with tisagenlecleucel (95% CI, 72%-90%). Of these patients, 98% achieved minimal residual disease (MRD)—negativity in the bone marrow.

"Now, with more follow-up, we see that patients who go into remission, remain in remission. That longer-term follow-up is very exciting to us. There’s a potential here for long-term disease control," said Grupp. "We're pleased by this long-term follow-up data."

Both the duration of response (DOR) and OS were significantly longer in patients who achieved MRD-negativity by next generation sequencing. The probability of DOR in patients with a complete response was 0.2 in the MRD-positive group and 0.8 in the MRD-negative arm. The probability of OS was 0.9 in the MRD-negative group and 0.35 in the MRD-positive arm.

"All but one patient was negative for minimal residual disease. If you're negative, you remain in remission about 80% of the time and if you're positive you remain in remission about 20% of the time. The same was seen for survival," Grupp said. "As we think about the role of transplant, this is a group of patients where I am wondering if they actually need transplant, and, in fact, a vast majority of patients did not have one."

In the longer-term assessment, a majority of adverse events (AEs) occurred within the first 8 weeks of treatment. The rate of cytokine release syndrome (CRS) of any severity was 77%, with 22% having a grade 3 event and 27% having a grade 4 event. A neurological event of any grade occurred in 39% of patients. Overall, 13% of patients a grade 3 neurological event and none had a grade 4 events. There were no cases of cerebral edema reported.

Other AEs of special interest included infection, which occurred in 43% of patients in the trial. The rate of grade 3 infection was 20% and 4% of patients had a grade 4 event. Additionally, cytopenias that did not resolve by day 28 occurred for 42% of patients, with 18% having a grade 3 event and 18% having a grade 4 event. Grade 3 tumor lysis syndrome occurred in 5% of patients.

"We're not seeing anything new in terms of toxicity," Grupp said. "There was a low infection rate, and some patients have cytopenias that do not resolve. There were very low neurologic events. This has been consistent across studies."

Based on an earlier analysis of the ELIANA trial, in August 2017, the FDA granted regular approval to tisagenlecleucel for the treatment of patients up to age 25 years with B-cell precursor ALL that was refractory or in second or later relapse. The agent is approved with a Risk Evaluation and Mitigation Strategy for CRS. Further studies continue to assess the agent across other blood cancers.

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. Presented at the 2018 ASH Annual Meeting, San Diego, CA, December 1-4, 2018. Abstract 895.

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