Abstract: TH-PO1163
Failure of Regulatory B Cells to Repopulate After Rituximab Associates with Lack of Efficacy in Renal Transplant Patients with CAMR: Evidence from the RituxiCAN-C4 Trial
Session Information
- Late-Breaking Clinical Trials Posters
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- No subcategory defined
Authors
- Dorling, Anthony, King's College London, London, United Kingdom
- Shiu, Kin Y., Royal Free Hospital, London, United Kingdom
- Mclaughlin, Laura, King's College London, London, United Kingdom
- Stringer, Dominic, King's College London, London, United Kingdom
- Tsui, Tjir-Li, Guy's & St Thomas' NHS Foundation Trust, London, london, United Kingdom
- Shaw, Olivia, Viapath, Guys Hospital, London, United Kingdom
- Brookes, Paul, Imperial College Healthcare NHS Trust, London, United Kingdom
- Burton, Hannah M.M., King's College London, London, United Kingdom
- Wilkinson, Hannah E., King's College London, London, United Kingdom
- Douthwaite, Hatty A A, Guy's & St Thomas' NHS Foundation Trust, London, london, United Kingdom
- Mclean, Adam, Imperial College Kidney & Transplant Institute, London, United Kingdom
- Hilton, Rachel, Guy's & St Thomas' NHS Foundation Trust, London, london, United Kingdom
- Griffin, Sian V., Heath Hospital Cardiff, Cardiff, United Kingdom
- Ball, Simon T., University Hospital Birmingham, Edgbaston, United Kingdom
- Baker, Richard James, SJUH, Leeds, United Kingdom
- Roufosse, Candice A., Imperial College Healthcare NHS Trust, London, United Kingdom
- Horsfield, Catherine J., Guy's & St Thomas' NHS Foundation Trust, London, london, United Kingdom
Background
Immune-mediated late failure of kidney allografts is a significant problem, usually presenting as progressive dysfunction with histological features of chronic antibody-mediated rejection (CAMR). RituxiCAN-C4 was an open-labelled randomised controlled phase IV clinical trial running in 13 UK centres from 2007-2017, to assess efficacy of Rituximab in stabilising graft function after failure of optimised oral immunosuppression.
Methods
Of 59 patients meeting eligibility criteria who underwent optimisation, 23 consented to randomisation, 11 to no additional treatment (control), and 12 to Rituximab. In the pre-specified second interim (per protocol) analysis of the 9 who received rituximab vs. 11 controls, there was no significant difference in the primary endpoint (short-term stability of function), so recruitment was halted in 2015. Follow-up ended in 2017.
Results
The median reduction in circulating B cells post Rituximab was 98.2% (IQR 3.8%), with no significant recovery in circulating B cells over 3 years. Analysis of remaining B cells showed normalisation of the proportions of different subpopulations, except for transitional cells expressing higher levels of CD24 and CD38, which remained disproportionately low compared to controls. ELISPOT analysis of indirect alloresponses to donor proteins in all 59 patients confirmed that B dependent CD4+ IFNγ production associated with greater decline in eGFR. Optimisation of immunosuppression that resulted in conversion to non-responsiveness or to anti-donor responses regulated by CD19+ or CD25+ cells was associated with slower decline in eGFR. Regulation by CD19+ cells associated with higher proportions of the same transitional B cells that failed to repopulate in Rituximab-treated patients, none of whom showed this pattern of ELISPOT responsiveness.
Conclusion
This analysis illustrates the importance of B cells and indirect alloresponses in CAMR, confirms the functional heterogeneity of B cells and association with eGFR decline in these patients, and suggests an explanation for the lack of efficacy of Rituximab in CAMR.
Funding
- Commercial Support – Roche provided the rituximab free of charge