Tisagenlecleucel Benefit Sustained in DLBCL Follow-Up

Richard T. Maziarz, MD

Tisagenlecleucel (Kymriah) continued to demonstrate durable objective response rates (ORR) with a median of 19 months of follow-up for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to updated findings from the phase II JULIET study presented at the 2018 ASH Annual Meeting.

At the updated analysis, the ORR was 54% (95% CI, 41%-62%) with the CD19-targeted CAR T-cell therapy. There was a complete remission rate of 40%, with the remainder of patients having a partial response. The median duration of response was not yet reach at the time of the analysis; however, senior investigator Richard T. Maziarz, MD, noted that 54% of the patients who initially had a partial response had converted to a complete response.

"This is a longer-term follow-up of preliminary, early data presented last year," said Maziarz, from the Oregon Health & Science Knight Cancer Institute. "This is 19 months' follow-up, and the reason this is important is because early on you always wonder if there is selection bias. As you move into 19 months, you're really looking at the natural history of the disease."

At the May 21, 2018, data cutoff there were 167 patients enrolled in the study, of which 115 had received treatment with a single dose of tisagenlecleucel at a median of 3.0 x 10⁸ CAR-positive T cells. Overall, 90% of patients enrolled in the study had received bridging therapy and 93% had received lymphodepleting chemotherapy prior to infusion of the CAR T cells. The median time from infusion to data cutoff was 19.3 months.

The median age of enrolled patients was 56 years (range, 22-76), and 23% were 65 or older. At baseline, three-fourth of patients (77%) had stage III/IV DLBCL and 17% had double or triple hit disease. More than half of patients (55%) had the germinal center subtype, with 43% having activated B-cell DLBCL. Nearly half of patients (49%) had undergone a prior stem cell transplant and 51% had received 3 or more prior therapies.

The 6-month relapse-free survival (RFS) rate was 66% (95% CI, 51%-78%), which remained consistent at 64% at both the 12- and 18-month data analyses (95% CI, 48%-76%). The median overall survival (OS) for all infused patients was 11.1 months but was not reached for those who achieved a complete remission to tisagenlecleucel. The 12-month OS rate was 48% (95% Ci, 38%-57%) and the 18-month OS rate was 43% (95% CI, 33%-53%).

"There are multiple subtypes in large cell lymphoma, it's a very complex disease. Across all the potential prognostic subgroups, we could not see a predicted group where tisagenlecleucel was favored or predicted to fail," said Maziarz. "In those who achieved a complete response, the median overall survival is not yet reached. What we see is that we're approaching a plateau, and we're definitely seeing a change in the natural history of the disease."

There were no new deaths reported since the prior assessment, and adverse events (AEs) remained consistent. Overall, 57% of patients experienced cytokine release syndrome (CRS) of any grade in the study, with 14% having a grade 3 event and 9% having a grade 4 event. The rate of neurological AEs was 20%, with 7% grade 3 and 4% grade 4.

However, Maziarz noted that the grading system used for these events likely resulted in an overestimation, as the University of Pennsylvania criteria were used and not the Lee criteria. Further studies are ongoing to uncover the true rates of AEs, he noted.

Other AEs of interested included prolonged cytopenias, which occurred in 45% of patients, and infection, which was present in 37% of patients. Additionally, 15% of patients experienced febrile neutropenia and 2% had tumor lysis syndrome.

“Before CAR-T cell therapy, achieving and maintaining a prolonged complete response in adult patients with relapsed or refractory DLBCL was incredibly rare, but now we are seeing Kymriah result in durable complete responses more than a year and a half after infusion,” lead author of the updated JULIET analysis, Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center, said in a press release. “Duration of response and a consistent safety profile are incredibly important data points, and the findings from this updated analysis further instill confidence in the continuing potential of Kymriah in the treatment of these patients.”

Based on an initial assessment of the JULIET study, in May 2018, the FDA approved tisagenlecleucel as a treatment for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. The agent continues to be assessed in various trials, including studies looking at health economics. Although most private insurers will reimburse for the medication, the Centers for Medicare & Medicaid Services still lag behind; however, Maziarz remained optimistic that a resolution could be in sight.

Schuster SJ, Bishop MR, Tam C, et al. Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel. Presented at the 2018 ASH Annual Meeting, San Diego, CA, December 1-4, 2018. Abstract 1684.

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