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Multicenter Study
. 2018 Dec 15;24(24):6175-6184.
doi: 10.1158/1078-0432.CCR-18-0758. Epub 2018 Sep 6.

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

Karen Thudium Mueller  1 , Edward Waldron  2 , Stephan A Grupp  3   4 , John E Levine  5   6 , Theodore W Laetsch  7   8 , Michael A Pulsipher  9 , Michael W Boyer  10 , Keith J August  11 , Jason Hamilton  12 , Rakesh Awasthi  13 , Andrew M Stein  14 , Denise Sickert  15 , Abhijit Chakraborty  2 , Bruce L Levine  16 , Carl H June  16 , Lori Tomassian  2 , Sweta S Shah  2 , Mimi Leung  2 , Tetiana Taran  2 , Patricia A Wood  2 , Shannon L Maude  3   4
Affiliations
Multicenter Study

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

Karen Thudium Mueller et al. Clin Cancer Res. .

Abstract

Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

Patients and methods: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

Results: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients >50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response.

Conclusions: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.

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Figures

Figure 1.
Figure 1.
Tisagenlecleucel cellular kinetics. Tisagenlecleucel cellular kinetics from a representative profile of a patient with pediatric B-ALL in the ELIANA study showing the initial expansion phase to day 28 (A) and day 300 (B). LLOQ, lower limit of quantitation.
Figure 2.
Figure 2.
Cellular kinetics of tisagenlecleucel transgene by response in the ELIANA study.
Figure 3.
Figure 3.
The impact of tocilizumab on tisagenlecleucel expansion and persistence. Days 0 to 28 (A) and days 0 to 600 (B) after tisagenlecleucel infusion. Persistence of tisagenlecleucel was observed for up to 457 days. Data presented are for an updated data cut with 68 patients who received tisagenlecleucel infusion. Day 548 corresponds with the month 18 study visit.
Figure 4.
Figure 4.
Tisagenlecleucel transgene levels by B-cell recovery time.
Figure 5.
Figure 5.
Cellular kinetics of tisagenlecleucel by relapse category and sustained response.
See this image and copyright information in PMC

References

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