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Tisagenlecleucel Demonstrates Durable Efficacy in Relapsed/Refractory DLBCL

May, Brandon

doi: 10.1097/01.COT.0000615280.50955.4b
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High-dose immunochemotherapy followed by autologous hematopoietic stem cell transplantation represents the current standard of care in patients with diffuse large B-cell lymphoma (DLBCL). Despite this standard, only a small proportion of patients undergo transplant, and approximately 10-15 percent of patients experience primary refractory disease within a 3-month period following therapy, whereas 20-35 percent of patients experience disease relapse (Curr Stem Cell Res Ther 2017;12(1):14-18; Blood 2015;125(1):22-32).

Prognosis is poor in patients who are unable to start high-dose chemotherapy and subsequently undergo transplant as second-line therapy. In these patients, there is a median overall survival (OS) of 4.4 months as well as 1-year OS of 23 percent and 2-year OS of 16 percent (Bone Marrow Transplant 2016;51:51-57).

CAR T Therapy

Efficacy of anti-CD19 CAR T-cell therapy tisagenlecleucel has been demonstrated in some studies of pediatric and adult patients with relapsed or refractory acute lymphoblastic leukemia (N Engl J Med 2014;371:1507-1517; Blood 2016;128:2801-2801. Abstract). These studies showed improvements in both remission rates as well as OS. Based on these data, the FDA approved tisagenlecleucel in patients with relapsed or refractory large B-cell lymphoma.

At the 2019 Society of Hematologic Oncology meeting, researchers presented findings from an analysis of data from the JULIET trial (NCT02445248), a single-arm, phase II study of centrally manufactured tisagenlecleucel in patients with relapsed or refractory DLBCL (Hematol Oncol 2019;37(S2):308-310). A previous analysis of the JULIET trial, published in the New England Journal of Medicine, found that a tisagenlecleucel infusion conferred high durable response rates in patients with relapsed or refractory DLBCL (2019;380(1):45-56).

The JULIET study population consists of adult patients who are ineligible for or had disease progression following autologous hematopoietic stem cell transplant. Prior to tisagenlecleucel infusion, patients were administered one cycle of lymphodepleting chemotherapy. During this period, patients received either one of two options: 1) bendamustine at 90 mg per square meter per day for a total of 2 days, or 2) fludarabine at 25 mg per square meter of body surface area and cyclophosphamide at 250 mg per square meter per day for a total of 3 days.

Overall response rate (ORR), defined as complete response (CR) plus partial response, comprised the primary endpoint of the JULIET trial. Secondary endpoints included incidence and severity of adverse events, time to response, duration of overall response, event-free survival, progression-free survival, and OS.

At time of data cut-off (Dec. 11, 2018), a total of 115 patients with relapsed or refractory DLBCL were infused, with 99 patients evaluable for the efficacy analysis. The ORR remained at 54 percent (95% CI, 43-64), whereas the CR rate reached approximately 40 percent. At a maximum follow-up period of almost 24 months from response onset, the median duration of response was not reached (95% CI, 10, NR).

Between 6 and 12 months, relapse was observed in three of the 31 patients who achieved a CR at 6 months. Only one patient relapsed beyond 12-month follow-up. In the overall cohort of 115 patients with relapsed or refractory DLBCL, the median OS was 10.3 months. The OS for patients who achieved CR was not reached.

Adverse event rates were also observed in a small proportion of patients treated with tisagenlecleucel. Approximately 23 percent of patients experienced severe grade 3/4 cytokine release syndrome (CRS), whereas 11 percent of patients experienced severe grade 3/4 neurological events (NE). It took a median of 3 days for CRS to occur and a median of 6 days for NE to occur. The researchers observed that the majority of patients with any grade NE also had CRS (83%), whereas more than half (62%) of patients with severe NE also had severe CRS. Severe CRS was associated with higher levels of C-reactive protein, ferritin, interferon-γ (IFNG), interleukin 2 (IL2), interleukin 6 (IL6), and interleukin 10 (IL10). There were similar—albeit less pronounced—increases in CRP, ferritin, IL2, IL6, and IL10 in patients with severe NE.

In patients with CRS and NE, there were increased peak cytokine levels within 1 month of infusion. This trend was substantially greater in patients who experienced severe CRS and NE. Cytokines peaked on days 6 through 9 in patients with CRS, and patients with severe CRS had early increases in IL2, IL6, and IFNG in the first 2 days after infusion with tisagenlecleucel.

Following lymphodepleting chemotherapy, low platelet counts, elevated lactate dehydrogenase, and below-normal albumin levels were observed. Low levels of these variables were also observed after infusion in patients with severe CRS. There was an upward trend of hepatic and kidney dysfunction-related analytes, which correlated with CRS progression. In patients with severe CRS, increases in these analytes peaked 2 weeks after infusion.

The study investigators noted that the study is limited by its short duration of follow-up, as well as the lack of a control group. They also added that they are currently conducting ongoing univariate and multivariate analyses based on patients' disease and clinical characteristics to predict the incidence of CRS and NE in this patient population.

Brandon May is a contributing writer.

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