CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results

Abstract

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.

Extended Data Figure 1:. Response of patients with relapsed and refractory lymphoma

(1A) Best response by day 100 post CAR T-cell infusion displayed by the cell products received. (1B) Overall survival (1C) progression free survival of the study patients separated by LBCL vs. MCL. The shaded region represents the pointwise 95% confidence interval of the survival estimate. CAR denotes chimeric antigen receptor; ORR denotes overall response rate; PD denotes progressive disease; LBCL denotes large B-cell lymphoma; MCL denotes mantle cell lymphoma; *One patient died of COVID-19 pneumonia at day 47 and did not have day 30 response assessment - this patient is included in the PD category.

Extended Data Figure 2:. Serum cytokine changes over time on study

Changes in the level of serum cytokines after anakinra administration separated by grade 0-2 ICANS vs. grade 3-4 ICANS. The smoothed solid lines over time in each plot represent a locally weighted scatterplot smoother, and the dashed lines represent the corresponding 95% confidence interval.

Figure 1.

Consort Diagram

Figure 2.. Rates of CRS and ICANS in the 31 patients treated with prophylactic anakinra.

(2A) Overall rate of CRS and ICANS. (2B) Rate of ICANS by grade and CD19-directed CAR T-cell product. (2C) Rate of CRS by grade and CD19-directed CAR T-cell product CRS denotes cytokine release syndrome; ICANS denotes immune effector-cell mediated neurotoxicity syndrome; axi-cel denotes axicabtagene ciloleucel; brexu-cel denotes brexucabtagene; tisa-cel denotes tisagenlecleucel.

Figure 3.. Response of patients with relapsed and refractory lymphoma.

(3A) Best response by day 100 post CAR T-cell infusion in the 31 patients treated with prophylactic anakinra by diseae subtype. (3B) Overall survival and (3C) progression free survial of the study patients. The shaded resion represents the pointwise 95% confidence interval of the survival estimate. CAR denotes chimeric antigen receptor; ORR denotes overall response rate; PD denotes progressive disease; LBCL denotes large B-cell lymphoma; MCL denotes mantle cell lymphoma; * One patient died of COVID-19 pneumonia at day 47 and did not have day 30 response assessment - this patient is included in the PD category

Figure 4:. Serum and CSF cytokine changes over time on study.

(4A) Change in the level of serum cytokines after anakinra adminstration (n=31). The orange smoothed solid lines over time in each plot represent a locally weighted scatterplot smoother, and the dashed lines represent the corresponding 95% confidence interval. All 31 patients contributed at least one cytokine value in each figure. (4B) Levels of CSF white blood cell (WBC) counts, and CSF protein counts before and after anakinra administration. For WBC and CSF protein counts, a total of 27 patients had an available pre-infusion value and 24 had a post-infusion value. (4C) Levels of cytokines in the CSF at baseline and 5-days after the adminstration of anakinra. A total of 15 patients had available pre-infusion cytokine value, and 15 patients had post-infusion values. For 4B and 4C, the black center line within the box represents the median, and the lower and upper edges of the box represent the 25% (Q1) and 75% (Q3) quantiles of the measurements. The upper whisker represents the minimum of either the highest count or 1.5 times the interquartile range (IQR) above Q3 (i.e., Q3+1.5*IQR). The lower whisker is defined similarly. Significance was assessed using a two-sided, partially matched Wilcoxon test. There was no adjustment for multiple comparisons. CSF denotes cerebrospinal fluid; WBC denotes white blood cell