Sencer Goklemez1, Sarfaraz Hasni2, Frances T Hakim1, Paolo A Muraro3, Filip Pirsl1, Jeremy Rose1, Sarfraz Memon1, Daniel F Fowler4, Seth M Steinberg1, Eva H Baker5, Sandya R Panch6, Ronald Gress1, Gabor G Illei7, Peter E Lipsky8, Steven Z Pavletic1. 1. Center for Cancer Research, National Cancer Institute. 2. Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. 3. Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK. 4. Rapa Therapeutics, Rockville. 5. Department of Radiology and Imaging Services; Clinical Center. 6. Center for Cellular Engineering, National Institutes of Health, Bethesda. 7. Viela Bio, Gaithersburg, MD. 8. AMPEL Bio Solutions and the RILITE Research Institute, Charlottesville, VA, USA.
Abstract
OBJECTIVE: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE. METHODS: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant. RESULTS: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody. CONCLUSION: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752. Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.
OBJECTIVE: Autologous haematopoietic cell transplantation (AHSCT) improves immunologic dysfunction in patients with SLE. However, the curative potential of this therapy remains uncertain. This study reports outcomes in SLE patients receiving a lymphodepleting, reduced intensity regimen for AHSCT in SLE. METHODS: Eight patients with SLE refractory to treatment, including i.v. cyclophosphamide (CYC), were enrolled. Five had LN and three CNS involvement as primary indications for transplant. Haematopoietic cell mobilization with CYC, G-CSF and rituximab was followed by collection of CD34+ positively selected cells. The conditioning regimen consisted of concurrent administration of CYC, fludarabine and rituximab. All immunosuppressive medications were discontinued at the start of mobilization and CS were rapidly tapered after the transplant. RESULTS: Five of eight patients achieved a complete response, including a decline in the SLEDAI to zero, which was sustained in four patients for a median of 165 months (range 138-191). One patient achieved a partial response, which was followed by relapse at month 18. Two patients with nephritis and underlying comorbidities in most organs had early deaths from infection and multiorgan failure. AHSCT resulted in profound lymphodepletion, followed by expansion of Treg cells and repopulation of naive T and B cells. Patients with a complete response showed a sustained suppression of the SLE-associated IFN-induced gene signature, marked depletion of memory and plasmablast B cells and resultant sustained elimination of anti-dsDNA antibody. CONCLUSION: Durable clinical and serologic remissions with suppression in the IFN gene signature can be achieved in refractory SLE following lymphodepleting AHSCT. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00076752. Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.
Authors: Wendelina J M Mackus; Florine N J Frakking; Annette Grummels; Laila E Gamadia; Godelieve J De Bree; Dorte Hamann; Rene A W Van Lier; Marinus H J Van Oers Journal: Blood Date: 2003-04-10 Impact factor: 22.113
Authors: Keith M Sullivan; Ellen A Goldmuntz; Lynette Keyes-Elstein; Peter A McSweeney; Ashley Pinckney; Beverly Welch; Maureen D Mayes; Richard A Nash; Leslie J Crofford; Barry Eggleston; Sharon Castina; Linda M Griffith; Julia S Goldstein; Dennis Wallace; Oana Craciunescu; Dinesh Khanna; Rodney J Folz; Jonathan Goldin; E William St Clair; James R Seibold; Kristine Phillips; Shin Mineishi; Robert W Simms; Karen Ballen; Mark H Wener; George E Georges; Shelly Heimfeld; Chitra Hosing; Stephen Forman; Suzanne Kafaja; Richard M Silver; Leroy Griffing; Jan Storek; Sharon LeClercq; Richard Brasington; Mary E Csuka; Christopher Bredeson; Carolyn Keever-Taylor; Robyn T Domsic; M Bashar Kahaleh; Thomas Medsger; Daniel E Furst Journal: N Engl J Med Date: 2018-01-04 Impact factor: 91.245
Authors: Frances T Hakim; Sarfraz Memon; Ping Jin; Matin M Imanguli; Huan Wang; Najibah Rehman; Xiao-Yi Yan; Jeremy Rose; Jacqueline W Mays; Susan Dhamala; Veena Kapoor; William Telford; John Dickinson; Sean Davis; David Halverson; Haley B Naik; Kristin Baird; Daniel Fowler; David Stroncek; Edward W Cowen; Steven Z Pavletic; Ronald E Gress Journal: J Immunol Date: 2016-09-30 Impact factor: 5.422
Authors: Paolo A Muraro; Marcelo Pasquini; Harold L Atkins; James D Bowen; Dominique Farge; Athanasios Fassas; Mark S Freedman; George E Georges; Francesca Gualandi; Nelson Hamerschlak; Eva Havrdova; Vassilios K Kimiskidis; Tomas Kozak; Giovanni L Mancardi; Luca Massacesi; Daniela A Moraes; Richard A Nash; Steven Pavletic; Jian Ouyang; Montserrat Rovira; Albert Saiz; Belinda Simoes; Marek Trnený; Lin Zhu; Manuela Badoglio; Xiaobo Zhong; Maria Pia Sormani; Riccardo Saccardi Journal: JAMA Neurol Date: 2017-04-01 Impact factor: 18.302