As reported by Stephen J. Schuster, MD, and colleagues in The Lancet Oncology, long-term outcomes of the pivotal phase II JULIET trial showed overall and complete response rates of 53% and 39% in adult patients with relapsed or refractory aggressive B-cell lymphomas treated with the T-cell immunotherapy tisagenlecleucel. The new data were based on a larger patient population than that reported in the primary analysis.

The trial supported the May 2018 approval of tisagenlecleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL)–not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma—after two or more lines of systemic therapy. The previously reported primary analysis showed a best overall response rate of 52% and complete response rate of 40% in 93 evaluable patients.  

Stephen J. Schuster, MD

Study Details

In the trial, 167 patients were enrolled from sites in 10 countries between July 2015 and November 2017. As of February 2020, 115 patients had received tisagenlecleucel infusion, constituting the full analysis set. Treatment consisted of a single intravenous infusion at a target dose of 5 × 10⁸ viable transduced chimeric antigen receptor (CAR) T cells.

Responses

Median follow-up was 40.3 months (interquartile range = 37.8­–43.8 months). On independent review committee assessment, objective response occurred in 61 patients (53.0%, 95% confidence interval [CI] = 43.5%–62.4%), with 45 (39.1%) having complete response as best overall response.

Median time to first response was 29.0 days (95% CI = 28.0–31.0 days). Median duration of response was not reached (95% CI = 10.0 months–not estimable), with the estimated proportion of patients maintaining response at 36 months being 60.4%.

Median progression-free survival was 2.9 months (95% CI = 2.3–5.2 months). Median overall survival was 11.1 months (95% CI = 6.6–23.9 months).

Among 37 patients with complete response at 3 months, 6 relapsed within 12 months. Of 34 patients with complete response at 6 months, 3 relapsed within 12 months. In post hoc analysis, median progression-free survival was not reached among patients with complete response at 3 or 6 months, and median overall survival was not reached among patients with complete response at 3 or 6 months or as best overall response.

Adverse Events

No new or unexpected safety signals were detected. The most common adverse events of any grade were cytokine-release syndrome (57%), anemia (48%), and pyrexia (36%). Adverse events of special interest occurring within the first 8 weeks postinfusion (apart from cytokine-release syndrome) included cytopenias not resolved by day 28 (45%, 34% grade ≥ 3), infections (37%, 19% grade ≥ 3), and neurologic events (20%, 11% grade ≥ 3).

The most common grade 3 and 4 adverse events were anemia (39%), decreased neutrophil count (34%), decreased white blood cell count (32%), decreased platelet count (28%), cytokine-release syndrome (23%), neutropenia (20%), and febrile neutropenia (17%). The most common treatment-related serious adverse events were cytokine-release syndrome (27%), febrile neutropenia (6%), pyrexia (5%), pancytopenia (3%), and pneumonia (3%). Three patients died within 30 days of infusion; none of the deaths was considered related to treatment.

The investigators concluded, “Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favorably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy).”

Dr. Schuster, of the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Novartis Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.