Real-World Study of Tisagenlecleucel in R/R B-Cell Non-Hodgkin Lymphomas Shows Efficacy, Safety

Daniel J. Landsburg, MD

Real-world data on the use of tisagenlecleucel (Kymriah) showed greater efficacy and a favorable safety profile, according to updated findings from a study of the Center for International Blood and Marrow Transplant Research (CIBMTR) registry that were presented during the 2021 ASH Annual Meeting and Exposition.¹ These findings were consistent with results of the pivotal phase 2 JULIET trial (NCT02445248) of patients with high-grade B-cell lymphoma (HGBL) or relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

At a median follow-up of 17.2 months (range, 6-34.7), the overall response rate (ORR) in all patients included in the updated analysis (n = 613) was 57.4% (n = 352). Moreover, 42.4% (n = 260) of patients had a best overall response (BOR) of a complete response (CR) and 15% (n = 92) had a BOR of a partial response (PR).

Among JULIET-eligible patients (n = 200), the ORR was 61% (n = 122); 44% (n = 88) had a CR as their BOR and 17% (n = 34) had a PR as their BOR.

Among JULIET-ineligible patients (n = 413), the ORR was 55.7% (n = 230); 41.6% (n = 172) had a CR as their BOR and 14% (n = 58) had a PR as their BOR.

“Data from the CIBMTR registry revealed favorable outcomes in terms of both survival and response, as well as toxicity, for patients treated with commercial tisagenlecleucel. These outcomes were similar to those seen in JULIET,” lead study author Daniel J. Landsburg, MD, vice chief of Quality and Safety in the Division of Hematology/Oncology, medical director of Infusion Services at the Hospital of the University of Pennsylvania, and an associate professor and physician at Penn Medicine, said in a presentation of the data.

DLBCL and HGBL are types of aggressive B-cell non-Hodgkin lymphoma in which patients who are not cured with first-line therapy tend to have poor prognoses.

Tisagenlecleucel is a CD19-directed autologous CAR T-cell therapy that was FDA approved in May 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 prior lines of systemic therapy.² The indication included patients with DLBCL not otherwise specified, HGBL, and DLBCL arising from follicular lymphoma.

The regulatory decision was based on findings from the JULIET trial, in which tisagenlecleucel induced a 53% ORR and 34.6% 12-month PFS rate in patients with heavily pretreated relapsed/refractory DLBCL (n = 115).³

Early data from the CIBMTR registry demonstrated similar real-world efficacy with tisagenlecleucel, as well as a more favorable safety profile compared with the data from the JULIET trial. During the 2021 ASH Annual Meeting and Exposition, longer-term real-world data were reported for a larger group of patients with DLBCL and HGBL, including those not meeting eligibility criteria for the JULIET trial.

The non-interventional, prospective, longitudinal study utilized the CIBMTR database to evaluate patients treated in the United States, Israel, and Canada who were infused with tisagenlecleucel and had at least 6 months of follow-up unless they died earlier.

Efficacy outcomes for assessment included ORR, CR/PR rates, progression-free survival (PFS), duration of response (DOR), and overall survival. Safety outcomes for assessment included cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).

The overall infused patient population (n = 682) comprised an efficacy set (n = 613) and a safety set (n = 625). The efficacy set consisted of JULIET-eligible patients (n = 200) and JULIET-ineligible patients (n = 413), as did the safety set (n = 202 and n = 423, respectively).

Reasons for JULIET ineligibility in the infused set included age less than 18 years (n = 1; 0.1%), ECOG performance status (PS) of 2 or higher (n = 137; 20.1%), ineligible disease histology (n = 38; 5.6%), radiographic CR at infusion (n = 55; 8.1%), less than 2 prior lines of therapy (n = 109; 16%), prior allogeneic hematopoietic stem cell transplant (allo-HSCT; n = 18; 2.6%), and comorbidities (n = 372; 54.5%). This translated to a total of 462 JULIET-ineligible patients (67.7%).

The median follow-up in all patients was 16.3 months (range, 6-34.7).

In the infused set, patients were a median age of 66.5 years (range, 14-91) at infusion, with the majority of patients (n = 377; 55.3%) being at least 65 years of age and 17.6% (n = 120) being at least 75 years of age. Most patients (n = 400; 58.7%) were male.

Most patients (n = 366; 53.7%) had relapsed disease while 38.3% (n = 261) had primary refractory disease. Patients had a median of 3 prior therapies (range, 0-11). Most patients (n = 545; 79.9%) had an ECOG PS of 0 or 1.

The majority of patients (n = 554; 81.2%) had DLBCL; 12.9% (n = 88) had HGBL, 11.4% (n = 78) of which was double- or triple-hit lymphoma, and 27.9% (n = 190) had transformed lymphoma, 3.8% (n = 26) of which was transformed from chronic lymphocytic leukemia. Regarding prior HSCT, 25.8% (n = 176) of patients had prior autologous HSCT, 1.6% (n = 11) had prior allo-HSCT, and 0.4% (n = 3) had both.

Moreover, most baseline patient demographics except for ECOG PS were similar between JULIET-eligible and JULIET-ineligible subgroups, Landsburg explained.

Additional results showed that the median time from receipt of leukapheresis product at the manufacturing site to shipment was 26 days (range, 24-32) in all patients, 26 days (range, 25-31) in JULIET-eligible patients, and 26 days (range, 24-32) in JULIET-ineligible patients. The rate of PR to CR conversion was 2%, 3%, and 1.5%, respectively.

By JULIET eligibility, the median PFS was 3.9 months (95% CI, 3.16-5.13) in JULIET-eligible patients, 3.9 months (95% CI, 3.29-4.93) in JULIET-ineligible patients, and 3.9 months (95% CI, 3.36-4.80) in all patients. By BOR, the median PFS was not evaluable (NE; 95% CI, 14.84-NE) with CRs (n = 260), 5.1 months (95% CI, 3.62-7.4) with PRs (n = 92), and 14.8 months (95% CI, 9.34-NE) with CR/PRs (n = 352).

The 12-month PFS rates were similar between JULIET-ineligible patients and the efficacy set, both reflecting similar rates as observed in the JULIET trial at 34.6%.

By JULIET eligibility, the median DOR was 10.9 months (95% CI, 4.44-NE) in JULIET-eligible patients, NE (95% CI, 7.14-NE) in JULIET-ineligible patients, and NE (95% CI, 7.2-NE) in all patients. By BOR, the median DOR was NE (95% CI, NE-NE) with CRs, 3.1 months (95% CI, 2.37-4.87) with PRs, and NE (95% CI, 7.2-NE) with CR/PRs.

“The 12-month DOR of 54% was similar between JULIET eligible- and -ineligible patients and was numerically lower than that seen in JULIET at 63%; however, it is worth noting the much narrower confidence interval in our cohort as expected from a larger patient sample size,” Landsburg said.

Regarding safety, any-grade CRS per American Society for Transplantation and Cellular Therapy (ASTCT) grading was observed in 51.8% of patients; 8% of patients had grade 3 or greater CRS, and 0.5% of patients had grade 5 CRS. Therapy for CRS was provided to 60.5% of patients overall; treatment interventions included tocilizumab (Actemra; 44.1%), corticosteroids (15.4%), siltuximab (Sylvant; 0.9%), and others (17.9%). The median time to onset of CRS was 4 days (range, 1-30), and the median time to resolution of CRS was 5 days (range, NE-NE).

“The rate of use of therapy was higher in the JULIET-ineligible subgroup. This may be because these patients were less fit and their clinicians felt they would not tolerate ongoing CRS or higher-grade CRS well and chose to use therapy to treat this,” Landsburg said.

Notably, the rates of grade 3 or higher CRS were lower in the CIBMTR population compared with the JULIET trial population at 8% vs 13.5%, respectively.

Tocilizumab was provided to 44.1% of patients with any-grade CRS; the maximum CRS grade tocilizumab was used in included grade 1 (39.9%), grade 2 (34.3%), grade 3 (12.6%), grade 4 (5.6%) and grade 5 (2.1%).

“While 44% of patients received tocilizumab for CRS, 74% of those patients received it for grade 1 or 2 CRS. In the JULIET study, tocilizumab was only recommended for grade 3 or 4 CRS. It is very possible that earlier use of tocilizumab prevented the onset of higher-grade CRS in this patient population,” Landsburg said.

Regarding ICANS, any-grade ICANS was observed in 19.8% of all patients; 7.7% of patients had grade 3 or higher ICANS and 0.8% of patients had grade 5 ICANS. Corticosteroids were provided to 58.9% of patients. The median time to onset of ICANS was 6 days (range, 1-33), and the median time to resolution of ICANS was 9 days (range, 6-11).

Notably, the rates of grade 3 or higher ICANS were lower in the CIBMTR population compared with the JULIET trial population at 7.7% vs 12.6%, respectively.

“Approximately two-thirds of patients in this analysis were deemed JULIET ineligible, suggesting that patients with relapsed/refractory aggressive lymphomas may benefit from commercial tisagenlecleucel even if they would not have met criteria for the JULIET study,” Landsburg concluded.

_References

_{1. Landsburg DJ, Frigault MJ, Hu ZH, et al. Real-world efficacy and safety outcomes for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin’s lymphoma (aBNHL) treated with commercial tisagenlecleucel: update from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. Presented at 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 429.}

_{2. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. May 1, 2018. Accessed December 12, 2021. https://bit.ly/3E0sxg5}

_{3. Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study.} Lancet Oncol. _{2021;22(10):1403-1415. doi:10.1016/S1470-2045(21)00375-2}