Long-term follow-up after lymphodepleting autologous haematopoietic cell transplantation for treatment-resistant systemic lupus erythematosus

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.

Keywords: SLE; cytokine; interferon; lymphodepletion; stem cell transplantation.

Fig. 1

Swimmer plot for clinical and autoantibody responses Swimmer plot summarizing the course of each individual patient over time including clinical responses and autoantibody (anti-dsDNA and ANA) status. The position of each letter (C and R) correspond to the time the event was first documented. Length of each bar represents the follow-up period for individual patients. Black arrows indicate the time when the patients remained in remission. Green and purple arrows indicate the time the patients were seronegative for anti-dsDNA and ANA, respectively. Patients 2, 3 and 6 shown were in sustained long-lasting complete remissions since AHSCT; patient 1 relapsed after 191 months. A colour version of the figure is available at Rheumatology online.

Fig. 2

Overall survival and SLE relapse-free survival after AHSCT Overall survival (OS) (A) and progression -free survival (PFS) (B) for all eight patients. Transplant-related mortality was 25%, whereas 50% (4/8) of patients had a complete response lasting for 11–15 years without any need for systemic immunosuppressive medications. Patient number 2 died >13 years after transplant from unknown causes. Patient number 1 relapsed after 16 years. For OS, five patients are censored, at 11.8, 13.3, 14.1, 14.1 and 16.0 years. For progression-free survival, two patients are censored at 11.8 and 14.1 years.

Fig. 3

Repopulation of lymphocytes after autologous lymphodepleting, reduced intensity conditioning transplant (A) CD4, CD8, NK and B cells. Medians shown as red bars. (B) Quantitative area plots of T cell subsets. [Naïve: CCR7+CD45RA+, blue; central memory: CCR7+CD45RA–, red; effector memory: CCR7–CD45RA–, green; T effector memory RA+: CCR7–CD45RA+, purple.] †Deceased. (C) Thymic-dependent generation of T cells as calculated as total sjTREC+ CD4 or CD8 T cells/ml, based on cells/ml and sjTREC/10⁵ T cells. Each line corresponds to a separate patient at baseline and at 5–6 years. TREC levels at DOT were estimated as <10³ TREC+ T cells/ml. (D) Recovery of CD4 Treg after transplant. Time course plot of the percentage of FoxP3+CD25+ Treg cells within gated CD4+ T cells in individual patients. Gap separates baseline Treg levels from post-transplant. Patient key for both (C) and (D): patient 1, blue; patient 2, brown; patient 3, green; patient 4, purple; patient 5, turquoise; patient 6, orange; patient 7, red; patient 8, black. (E) Repopulation of B cells during the first 18 months after transplant. Double negative: IgD–CD27–, black. Naïve: IgD+CD27–, red; IgM memory: IgD+CD27+, blue; chain-switched memory: IgD–CD27+, green; plasmablasts/plasma cells: IgD–CD27+CD38++, purple. †Deceased. A colour version of the figure is available at Rheumatology online. sjTREC: signal joint T cell receptor rearrangement excision circles.

Fig. 4

Expression of Type I IFN-induced genes in circulating monocytes at baseline and 5–6 years after transplant. Expressed as fold-change in gene expression as compared with median expression of these genes in 20 healthy control donors (ND). Patients in remission after AHSCT whether drug-free (patients 1, 2 and 6) or under maintenance dose steroids (patient 5) showed a significant decline in expression of Type I IFN-induced genes; patient 7, who continued to have lupus symptoms, had elevated expression of these genes. A colour version of the figure is available at Rheumatology online. (IFI44L, blue; IFIT1, red; IFITM3, green; IRF7, purple; MX1, turquoise; PLSCR1, orange; RSAD2, gray; XAF1, brown). AHSCT: autologous haematopoietic stem cell transplantation.