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. 2017 Nov 23;130(21):2317-2325.
doi: 10.1182/blood-2017-06-786129. Epub 2017 Sep 21.

Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

Karen Thudium Mueller  1 , Shannon L Maude  2   3 , David L Porter  3 , Noelle Frey  3 , Patricia Wood  1 , Xia Han  1 , Edward Waldron  1 , Abhijit Chakraborty  1 , Rakesh Awasthi  1 , Bruce L Levine  3 , J Joseph Melenhorst  3 , Stephan A Grupp  2   3 , Carl H June  3 , Simon F Lacey  3
Affiliations

Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

Karen Thudium Mueller et al. Blood. .

Abstract

Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: E.W. and R.A. are employees of Novartis; K.T.M., P.W., X.H., and A.C. are employees of and own equity in Novartis. S.L.M. received consultancy fees from and participated on advisory boards for Novartis. D.L.P. received research support from Novartis, participated on advisory boards for Servier, has a spouse that is an employee of and owns equity in Genentech, and has a patent related to the submitted work. N.F. received research support from Novartis. B.L.L. received grants from Novartis and personal fees from GE Healthcare and holds patents related to the submitted work. J.J.M. received research support from Novartis and holds patents related to the submitted work. S.A.G. received grants and consultancy fees from Novartis and holds patents related to the submitted work. C.H.J. received grants from Novartis and holds patents related to the submitted work. S.F.L. received grants from Novartis and speaking fees from Genentech.

Figures

Figure 1.
Figure 1.
CTL019 cellular kinetics. CTL019 cellular kinetics from a representative profile from a patient with pediatric B-ALL showing the initial expansion phase to day 28 (A) and day 780 (B). (C) Time course of levels of CTL019 transgene by qPCR and %CD3+ CTL019+ by flow cytometry for 3 patient groups: adult ALL, CLL, and pediatric B-ALL. LLOQ, lower limit of quantitation. CR/CRi, blue lines; PR/PRi, gold lines; NR/PD, red lines.
Figure 2.
Figure 2.
Relationship between exposure and expansion of CTL019 cells and response category in pediatric B-ALL, adult ALL, and CLL. (A) AUC0-28d. (B) Cmax. Dots represent the mean, and whiskers represent the standard error.
Figure 3.
Figure 3.
Mean (CV%) CTL019 transgene. (A) Copies of CTL019 transgene in PB, BM, and CSF during the first 6 months after infusion. (B) CTL019 transgene in CSF at day 28 by transient neuropsychiatric event. α for 1-way analysis of variance multiple comparisons test was 0.05. Grade 0 vs grade 1/2 neurological events, P = .5770; grade 0 vs grade 3/4 neurological events, P = .3591; grade 1/2 vs grade 3/4 neurological events, P = .9457.
Figure 4.
Figure 4.
Relationship between maximal CTL019 expansion, preinfusion tumor burden, and grade of CRS and neurologic events in pediatric B-ALL. (A) CRS grade. (B) Neurologic event grade. The numbers presented represent the highest grade of CRS or neurologic events observed (0/1/2/3/4). Gray dots represent the mean, and whiskers represent the standard error.
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Comment in

  • Road trip to remission with CARs.
    Jaglowski SM. Jaglowski SM. Blood. 2017 Nov 23;130(21):2240. doi: 10.1182/blood-2017-10-808584. Blood. 2017. PMID: 29170193 No abstract available.

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