Background/Purpose:

Over the past two decades, approximately 200 patients with severe systemic lupus erythematosus(SLE) have received autologous hematopoietic stem cell transplants (autoHSCT). More than half of these patients achieved clinical remission, but the duration of clinical benefit is variable and not well defined. We report long term clinical outcomes of eight refractory SLE patients in whom B cell depletion was combined with a reduced intensity T cell lymphoablative  conditioning regimen before autoHSCT.

Methods:

Eight patients were enrolled with active SLE despite prior treatment with IV cyclophosphamide (CYC): 2 had transverse myelitis, 1 retinal vasculitis and 5 WHO Class IV nephritis. Stem cell mobilization consisted of 2,000 mg/m² CYC, 750 mg/m² rituximab (RTX) and G-CSF. The conditioning regimen consisting of 750 mg/m² RTX, 4.8 g/m² CYC and 120 mg/m² fludarabine was followed by CD34+ selected stem cell infusion and G-CSF.

All immunosuppressive medications and hydroxychloroquine were discontinued at the start of mobilization and steroids were rapidly tapered off after the transplant. Clinical response was evaluated by organ specific response criteria. Disease activity indices (SLEDAI and SLAM) were used to assess overall lupus activity. The primary endpoint was complete response (CR) at 24 months defined as no lupus activity and no treatment for lupus (including HCQ and steroids).

Immune depletion and reconstitution was followed by multiparameter flow cytometry.

Results:

Of the 8 patients, there were 2 early infectious deaths (one from diffuse alveolar damage associated with coronavirus infection, one from mycobacterial meningoencephalitis) at 6 and 5 months post autoHSCT, respectively in subjects with no signs of active SLE. Four patients have had no disease activity in the 7 years of follow up and continue to have SLEDAI of 0 since 3 months after auto-HSCT. Two patients had lupus flares (at 6 and 18 months post-HSCT) which was subsequently well controlled requiring only modest doses of immunosuppressive  medications (one on prednisone <10 mg/day and one on daily azathioprine).  Six patients had no evidence of serological disease activity post autoHSCT, whereas one early response patient and one patient who flared at 6 months  continued to have positive  ANA and anti-SSA antibody with negative anti-ds-DNA antibody.

In responding patients, autoHSCT resulted in a loss of memory B cells and plasma B cells and recovery of naïve T and B cell populations in the first year after transplant. Notably, in contrast, the patient who flared at 6 months had an early reappearance of circulating plasma cells that preceded the flare.

Conclusion:

The novel regimen that included B cell depletion, modified immunoablation and autoHSCT resulted in sustained medication free remission in one half of the refractory SLE patients and a marked reduction in disease activity in another quarter. There were 2 (25%) deaths from infection, although these patients had no evidence of active SLE at the time of death. Whereas long term remission of SLE activity appears possible with this approach, additional studies are required to assess risk: benefit ratio and the appropriate patient population to treat.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lymphoablation-including-b-cell-depletion-and-autologous-hematopoietic-stem-cell-transplantation-leads-to-long-remissions-in-treatment-resistant-systemic-lupus-erythematosus-patients/