Phase II JULIET Study Continues To Show Benefit of Tisagenlecleucel in DLBCL

Jason Westin, MD

Jason Westin, MD

Recent updates to the JULIET study, presented at the 2019 SOHO Annual Meeting, show that tisagenlecleucel (Kymriah) has sustained benefit throughout the course of the trial with high response rates, and long duration in adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

JULIET is a single-arm open-label global phase II trial (NCT02445248) of tisagenlecleucel in adult patients with relapsed/refractory DLBCL who were ineligible for or had failed autologous stem cell transplant.

Coauthor Jason Westin, MD, leader of the DLBCL research team at the University of Texas MD Anderson Cancer Center, said that at a median follow-up of 26 months, the median duration of response had not been reached for patients in the main cohort. The overall response rate (ORR) was 54% (95% CI, 43%-64%) with a complete response (CR) rate of 40%. The median overall survival was 10.3 months.¹

Those results are in line with 14-month data presented by Peter Borchmann MD, of the University Hospital of Cologne at the 2018 European Hematology Association Congress. ORR then was 52% (95% CI, 41%-62%) with a CR rate of 40%.²

Westin et al noted a plateau in progression-free survival. Of 34 patients who had CR at 3 months, 6 relapsed within 12 months and 1 relapsed beyond 12 months.

Westin said occurrences of cytokine release syndrome (CRS) and neurological adverse events (AEs) were consistent with previous findings. Of 115 patients included in this analysis, 57.4% experienced any CRS and 22.6% experienced grade 3/4. Twenty percent experienced any-grade neurological AEs and 11.3% experienced grade 3/4.

At the 14-month analysis, 22% of patients experienced grade 3/4 CRS while 12% experienced grade 3/4 neurological AEs.

Investigators observed what appears to be a correlation between neurotoxicity and CRS. Eighty-three percent of patients who experienced any-grade neurotoxicity also developed CRS. Sixty-two percent of patients with severe neurotoxicity also developed severe CRS.

Of the 49 patients who did not have CRS, only 4 had any-grade neurotoxicity. Of 66 patients with any-grade CRS, 19 went on to develop any-grade neurotoxicity.

“Patients who did not have CRS generally did not have neurotoxicity,” Westin said. “In fact, the opposite is also true that in patients who did have neurotoxicity, 83% of them also had CRS. This is a pretty good correlation of neurotoxicity with CRS, not so much for CRS with neurotoxicity. A significant number of patients had CRS without neurotoxicity.”

The median time to onset of CRS and neurological AEs was 3 and 6 days, respectively.

A significant percentage of cytopenias resolved to grade ≤2 at 6 months, including 100% of both responders and all patients with cytopenias for white blood cells and hemoglobin. The majority of neutrophils and platelets also resolved to grade ≤2.

“Lymphocytes, interestingly, about half the patients are still grade 2 or greater at 6 months,” Westin said. “This is why it's important to consider prophylaxis for our patients.”

He went on to say that investigators have been working to discover a biomarker for CRS and neurotoxicity. Westin and his team analyzed ferritin, C-reactive protein, interleukins 6 and 10, tumor volume, LDH level, and albumin. Baseline LDH level was the only significant predictor for CRS in both univariate (OR, 3.454; 95% CI, 1.983-6.017) and multivariate (OR, 3.625; 95% CI, 1.72-7.642;P= .001) analyses.

No marker was a significant predictor for neurotoxicity. “We still struggle to identify which patients will develop neurotoxicity,” Westin said.

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. Based on earlier findings from the JULIET study, the FDA approved tisagenlecleucel in May 2018 for use in adult patients with relapsed/refractory large B-cell lymphoma—including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.

References

1. Bachanova V, Westin J, Tam C. Correlative analyses of cytokine release syndrome and neurological events in tisagenlecleucel-treated relapsed/refractory diffuse large B-Cell lymphoma patients. Presented at: the SOHO 2019 Annual Meeting; September 11-14, 2019; Houston, Texas. Abstract ABCL-278.
2. 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). Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S799.