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Mesenchymal stromal cells for steroid-refractory acute GvHD

Bone Marrow Transplantation volume 52, pages 1577–1579 (2017)Cite this article

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Treatment of patients developing steroid-refractory acute GvHD (SR-aGVHD) after allogeneic hematopoietic cell transplantation (HCT) remains a major therapeutic challenge. Mesenchymal stromal cells (MSC) have been used in this setting for over a decade. While many factors have been reported to play a role in response rates to MSC, including cell dose, culture passages, culture media and time to intervention, the overall effectiveness and optimal positioning of MSC in the management of patients with SR-aGVHD remains a matter of discussion.1, 2, 3, 4, 5, 6 Here we present a single center experience on early intervention with MSC in patients with SR-aGVHD leading to high overall and complete response (CR) rates associated with improved overall survival, which contributes to the body of evidence in this field.

Allogeneic HCT recipients with grade II–IV (Glucksberg modified criteria) SR-aGVHD were eligible for this study. Refractoriness to steroids was defined as: (1) progression after three days of treatment with 2 mg/kg methylprednisolone; (2) no response at day seven, or (3) no partial response at day 14. Patients were intended to receive a minimum of four MSC infusions given twice weekly. When CR was not achieved, additional weekly infusions were allowed. MSC production and administration was approved by the Institutional Ethics Committee and the National Regulatory Agency (EudraCT 2010-022316-39; 2005-005075). Third-party allogeneic clinical-grade MSC were isolated from bone marrow, cultured, expanded and cryopreserved in our Cell Production Unit following GMP standards, as previously described.7 Patients were treated from 2006 to 2014. From 2011, fetal calf serum (FCS) was replaced with platelet lysate (PL), obtained from 5–10 donor pooled apheresis frozen at −80 °C and then thawed at 37 °C.8, 9, 10 Harvested MSC were required to comply with previously defined criteria:11 spindle-shaped morphology and >90% cells expressing CD73, CD90, CD105, CD166 and HLA class I antigens and <10% expressing CD31, CD34, CD45, CD80 and HLA class II antigens by immune-phenotype (FC-500, Beckman Coulter, Madrid, Spain). MSC units were administered immediately after thawing. The primary endpoint was response to treatment at day 28 after the first MSC infusion, classified as CR (resolution of all aGVHD symptoms in every organ affected), partial response (PR; reduction of manifestations of aGVHD in at least one overall grade according to Glucksberg modified criteria) and no response (NR; progressive disease, stable disease or minimal response which does not reach criteria for PR). Secondary endpoints included response to treatment at day 90, survival rates at days 28 and 90, cause of death and longer-term overall survival (OS) as a time-dependent variable. Absolute and relative frequencies were used to describe categorical variables, median, range and interquartile range (IQR) for continuous variables, and the Chi-square or Fisher exact tests for categorical variable group comparisons. The probability of OS was estimated by the Kaplan-Meier method and log-rank test. Stata/IC version 14 (StataCorp LP; College Station, TX, USA) was used for statistical analysis. Reported P-values are two-sided and were accepted as statistically significant if <0.05.

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Acknowledgements

Grants from EC Framework Programme 6 (AlloStem IP, contract LSHB-CT-2004-503319), Spanish Fondo de Investigaciones Sanitarias (PIO3/0961, PIO4/2794, PS09/1736), FIBHUPH and Fundación Lair.

Author contributions

CFM, RGD and JRCM are responsible for the conception and design of the study and wrote the initial draft of this manuscript. JRCM, MNF and RFD reviewed all text and figures. All authors contributed to the execution of the study, the analysis and/or interpretation of the data, reviewed and approved the manuscript contents for publication.

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  1. C Fernández-Maqueda and R Gonzalo-Daganzo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Hospital Universitario Puerta de Hierro, Instituto de Investigación Puerta de Hierro (IDIPHIM), Majadahonda, Madrid, Spain

    C Fernández-Maqueda, R Gonzalo-Daganzo, C Regidor, T Martín-Donaire, R Sánchez, J L Bueno, G Bautista, A De Liglesia, Y Gutiérrez, M García-Berciano, R Forés, M N Fernández, R F Duarte & J R Cabrera-Marín

  2. Department of Clinical Biostatistics Unit, Hospital Universitario Puerta de Hierro, Instituto de Investigación Puerta de Hierro (IDIPHIM), Majadahonda, Madrid, Spain

    A Royuela

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  1. C Fernández-Maqueda
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  15. J R Cabrera-Marín
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Corresponding author

Correspondence to J R Cabrera-Marín.

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Fernández-Maqueda, C., Gonzalo-Daganzo, R., Regidor, C. et al. Mesenchymal stromal cells for steroid-refractory acute GvHD. Bone Marrow Transplant 52, 1577–1579 (2017). https://doi.org/10.1038/bmt.2017.177

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