Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells

L. C J Te Boome; C. Mansilla; L. E. Van Der Wagen; C. A. Lindemans; E. J. Petersen; E. Spierings; K. A. Thus; K. Westinga; M. Plantinga; M. Bierings; A. E C Broers; M. L H Cuijpers; G. W. Van Imhoff; J. J. Janssen; C. Huisman; S. Zeerleder; G. Huls; J. J. Boelens; N. M. Wulffraat; I. C M Slaper-Cortenbach; J. Kuball

doi:10.1038/leu.2015.89

Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells

L. C J Te Boome, C. Mansilla, L. E. Van Der Wagen, C. A. Lindemans, E. J. Petersen, E. Spierings, K. A. Thus, K. Westinga, M. Plantinga, M. Bierings, A. E C Broers, M. L H Cuijpers, G. W. Van Imhoff, J. J. Janssen, C. Huisman, S. Zeerleder, G. Huls, J. J. Boelens, N. M. Wulffraat, I. C M Slaper-CortenbachJ. Kuball^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

Original language	English
Pages (from-to)	1839-1846
Number of pages	8
Journal	Leukemia
Volume	29
Issue number	9
DOIs	https://doi.org/10.1038/leu.2015.89
Publication status	Published - 1 Jan 2015

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Te Boome, L. C. J., Mansilla, C., Van Der Wagen, L. E., Lindemans, C. A., Petersen, E. J., Spierings, E., Thus, K. A., Westinga, K., Plantinga, M., Bierings, M., Broers, A. E. C., Cuijpers, M. L. H., Van Imhoff, G. W., Janssen, J. J., Huisman, C., Zeerleder, S., Huls, G., Boelens, J. J., Wulffraat, N. M., ... Kuball, J. (2015). Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells. Leukemia, 29(9), 1839-1846. https://doi.org/10.1038/leu.2015.89

@article{66ddafdef71f4ef6b5f17fdcc7ef517e,

title = "Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells",

abstract = "We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.",

author = "{Te Boome}, {L. C J} and C. Mansilla and {Van Der Wagen}, {L. E.} and Lindemans, {C. A.} and Petersen, {E. J.} and E. Spierings and Thus, {K. A.} and K. Westinga and M. Plantinga and M. Bierings and Broers, {A. E C} and Cuijpers, {M. L H} and {Van Imhoff}, {G. W.} and Janssen, {J. J.} and C. Huisman and S. Zeerleder and G. Huls and Boelens, {J. J.} and Wulffraat, {N. M.} and Slaper-Cortenbach, {I. C M} and J. Kuball",

year = "2015",

month = jan,

day = "1",

doi = "10.1038/leu.2015.89",

language = "English",

volume = "29",

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journal = "Leukemia",

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Te Boome, LCJ, Mansilla, C, Van Der Wagen, LE, Lindemans, CA, Petersen, EJ, Spierings, E, Thus, KA, Westinga, K, Plantinga, M, Bierings, M, Broers, AEC, Cuijpers, MLH, Van Imhoff, GW, Janssen, JJ, Huisman, C, Zeerleder, S, Huls, G, Boelens, JJ, Wulffraat, NM, Slaper-Cortenbach, ICM & Kuball, J 2015, 'Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells', Leukemia, vol. 29, no. 9, pp. 1839-1846. https://doi.org/10.1038/leu.2015.89

TY - JOUR

T1 - Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells

AU - Te Boome, L. C J

AU - Mansilla, C.

AU - Van Der Wagen, L. E.

AU - Lindemans, C. A.

AU - Petersen, E. J.

AU - Spierings, E.

AU - Thus, K. A.

AU - Westinga, K.

AU - Plantinga, M.

AU - Bierings, M.

AU - Broers, A. E C

AU - Cuijpers, M. L H

AU - Van Imhoff, G. W.

AU - Janssen, J. J.

AU - Huisman, C.

AU - Zeerleder, S.

AU - Huls, G.

AU - Boelens, J. J.

AU - Wulffraat, N. M.

AU - Slaper-Cortenbach, I. C M

AU - Kuball, J.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

AB - We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

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U2 - 10.1038/leu.2015.89

DO - 10.1038/leu.2015.89

M3 - Article

AN - SCOPUS:84929119715

SN - 0887-6924

VL - 29

SP - 1839

EP - 1846

JO - Leukemia

JF - Leukemia

IS - 9

ER -

Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells

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