Tocilizumab Resolves CRS in Pediatric B-ALL Without Reducing Tisagenlecleucel Efficacy

Tocilizumab (Actemra) resolved cytokine release syndrome (CRS) in patients with relapsed/refractory pediatric B-cell acute lymphoblastic leukemia (B-ALL) without reducing the efficacy of tisagenlecleucel (Kymriah), according to results presented in a poster at the 2018 American Society of Pediatric Hematology/Oncology Conference.¹

Investigators reviewed data collected on patients infused with tisagenlecleucel in the pivotal ELIANA trial (N = 75). A total of 58 patients developed CRS following infusion, 28 (48.3%) of whom received tocilizumab. Twenty-six patients were included in the pharmacokinetic (PK) analysis.

Tocilizumab, an interluken-6 receptor (IL-6R) antagonist, resolved grade 3/4 CRS, including fever, within a median of 5 days.

Among those who had complete remission or complete remission with incomplete blood count recovery (CR/CRi), the geometric mean AUC of tisagenlecleucel transgene at 28 days postinfusion was 358% higher in patients who received tocilizumab, and the maximum tocilizumab concentration (C_max) was 216% higher.

Investigators concluded that tocilizumab levels in this patient population were similar to those reported for pediatric patients receiving the drug for indications outside of oncology, and that tocilizumab did not disrupt tisagenlecleucel expansion.

In April 2017, the FDA approved tocilizumab for the treatment of moderate to severe CRS associated with chimeric antigen receptor (CAR) T-cell therapy in patients aged 2 years or older. Results from a retrospective analysis of pooled data from 45 pediatric and adult patients treated in T-cell therapy clinical trials showed that the agent induced an overall response rate of 69% (95% CI, 53-82).²

Overall response was defined as resolution of CRS within 14 days with ≤2 doses of tocilizumab. Patients were only allowed to use tocilizumab or corticosteroids.

In this analysis, investigators evaluated patient serum samples that were quantified with validated assays to describe the PK of tocilizumab and the PD of soluble IL-6R levels. Investigators used noncompartmental analysis methods to determine C_max.

Median patient age in the trial was 11 years (range, 3-23) and 61% had undergone prior stem cell transplantation. Eight percent had primary refractory disease and 92% had relapsed disease.

Tocilizumab dose was based on approved nononcological pediatric indications—the drug is indicated for the treatment of active polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis in patients aged 2 years or older. Patients weighing <30 kg received a dose of 12 mg/kg of tocilizumab at the onset of CRS, while those who were ≥30kg received an 8 mg/kg dose. The maximum dose was 800 mg.

Seventeen (29.3%) patients with CRS received a single dose of tocilizumab, 8 (13.8%) received 2 doses, and 3 (5.2%) received 3 doses. All 19 patients with grade 4 CRS and 8 of 16 (50%) with grade 3 CRS received at least 1 dose.

After the first tocilizumab dose (range, 6.94-12.0 mg/kg), the mean C_max was 111.0 ± 30.6 µg/ml. The mean C_max after the second dose (range, 8.0-12.0 mg/kg) was 265.0 ± 376.0 µg/ml.

In patients treated with tocilizumab, the geometric mean exposure to tisagenlecleucel was 788,000 copies/µg of DNA. That represents a 282% increase compared with patients who did not receive the drug.

Soluble IL-6R levels increased with the first dose and remained elevated following the second dose.

Tisagenlecleucel became the first FDA-approved CAR T-cell therapy in August 2017 when the agency authorized the treatment for patients up to 25 years of age with B-ALL that is refractory or in second or later relapse.

The approval was based on phase II results from the single-arm ELIANA trial. At a median follow-up of 13.1 months, tisagenlecleucel induced an ORR of 81% in children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia ALL.³

In an analysis of 75 infused patients with 3 or more months of follow-up, 60% of patients achieved CR and 21% of patients achieved complete remission with incomplete blood count recovery following tisagenlecleucel infusion.

Based on results from the JULIET study, tisagenlecleucel received an FDA approval in April of this year for use in adult patients with relapsed/refractory large B-cell lymphoma—including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.⁴

References

1. Awasthi R, Lee C, Bittencourt H, et al. Pharmacokinetics and pharmacodynamics of tocilizumab for the management of cytokine release syndrome (CRS) in pediatric and young-adult patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (CTL019). Presented at: the 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, PA. Poster 709.
2. FDA approves Genentech’s Actemra (tocilizumab) for the treatment of CAR T cell-induced cytokine release syndrome [news release]; 2018. https://www.gene.com/media/press-releases/14679/2017-08-30/fda-approves-genentechs-actemra-tocilizu. Accessed May 11, 2018.
3. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018; 378:439-448.
4. Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 577.