Tisagenlecleucel in patients with R/R DLBCL without measurable disease at infusion

CD19 chimeric antigen receptor (CAR) T-cell therapy, tisagenlecleucel (tis) demonstrated efficacy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) without detectable disease after bridging or salvage therapies, according to a post hoc analysis of a small group of patients excluded from previous analysis of the JULIET study. Michael R. Bishop from the University of Chicago Medicine, Chicago, IL, US, and colleagues published the findings on July 23, 2019, in Blood Advances.¹

Currently, tis is indicated for patients with R/R DLBCL, and R/R pediatric and young adult acute lymphoblastic leukemia (ALL). The approval in DLBCL was based on the results from a phase II multicenter study JULIET (NCT02445248), which demonstrated an objective response rate of 52%, with a 40% complete response (CR) rate.² The ability of tis to expand, in patients without measurable disease before infusion, has not yet been established. In this analysis, a subset of seven patients with R/R DLBCL, who had CR after bridging therapy before receiving CAR T-cell infusion, was excluded from the former efficacy analysis. This article reports a post hoc analysis of tis expansion and persistence, as well as its safety and outcomes in this subset of patients.

Study design and patient characteristics

Adult patients with at least two prior lines of therapies, ineligible for or relapsed after autologous stem cell transplantation, were included in the study. Disease status and treatment response were assessed using positron emission tomography. All seven patients received bridging therapy, followed by lymphodepleting chemotherapy before a single infusion of tis with a target dose of 5 x 10⁸ viable CAR T-cells. 

Table 1. Baseline patient characteristics.

Characteristics

Patients in this subset

(n= 7)

JULIET patients²

(n= 111)

Median Age (years)

64

56

Sex

Female

Male

 

85.7%

14.3%

 

35.5%

64.5%

Type of disease

DLBCL

Transformed FL

 

86%

14%

 

79%

19%

Disease stage

I

II

III

IV

 

43%

0%

29%

29%

 

7%

17%

20%

56%

IPI risk factors

≥ 2

< 2

 

57%

43%

 

72%

28%

Disease status

Relapsed

Refractory

 

100%

0

 

45%

55%

Main findings

• The mean absolute lymphocyte counts before and after lymphodepletion were similar between the seven patients and overall JULIET population

• Tis rapidly expanded in vivo in all seven patients without measurable disease during the first 28 days after infusion

• Transgene levels were detected for approximately 2 years, median time was 351 days (190–693 days) and expected to rise with longer follow-up

• Median peak expansion transgene level at 5760 copies/µg (112%) was lower than the result from the overall JULIET trial of 5790 copies/µg (291%)

• The median time to peak expansion (9 days) was similar to that the rest of the patients in the JULIET study

• Median follow-up was 14.5 months

• All 7 patients in the subset remained in CR after 3 months, and five patients for more than 12 months

• Two patients experienced PD, one on day 274, and one on day 196

• Median time from last bridging therapy to the start of lymphodepleting chemotherapy was longer for the 7 patients than the overall JULIET population (44 and 24 days respectively)

Tis was similarly tolerated by the subset of seven patients as by the overall JULIET population. There were no deaths due to CAR T-cell therapy, CRS, cerebral edema, or neurotoxicity. Two patients experienced grade 2 cytokine release syndrome (CRS) and further two patients grade 3. The median duration of CRS was 5 days and did not require administration of steroids or tocilizumab. One patient experienced grade 1 neurologic events.

Conclusions

These results demonstrate the potential efficacy of tis in patients with R/R DLBCL without detectable disease after bridging or salvage therapies with good toxicity profile. The majority of patients in this subset remained progression-free for longer than anticipated with bridging therapy alone, suggesting that CAR T-cells can expand in response to residual disease undetected by PET imaging.

These encouraging data provide preliminary evidence for the use of tis as consolidative therapy for patients with relapsed and high-risk DLBCL in CR. However, the efficacy of this approach needs to be confirmed in further clinical trials involving a larger cohort of patients.