Hematopoietic stem cell transplantation for severe and refractory lupus

Abstract

Objective. To determine the safety and long-term efficacy of immune ablation and autologous hematopoietic stem cell transplantation (HSCT) in severe systemic lupus erythematosus (SLE).Methods. Fifteen patients with persistently active SLE after intravenous (IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells were mobilized with CYC (2.0 gm/m 2 ) and granulocyte colonystimulating factor (5 g/kg/day). Lymphocytes were depleted from the graft by selection of CD34-positive cells. The conditioning regimen used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE Disease Activity Index (SLEDAI), serum complement levels, serologic features, function of diseased organs, and immunosuppressive medication requirements.Results. Fifteen patients with persistent, severe SLE, 7 of whom were critically ill, were treated. No deaths occurred following treatment. The median followup after HSCT has been 36 months (range 12-66 months). All patients demonstrated a gradual, but marked, improvement. The SLEDAI score has declined to <5 in 12 patients. Complement and anti-doublestranded DNA levels have normalized and marked improvements in end organ function have occurred in all subjects. Of the 12 patients followed up for >1 year after HSCT, 10 have discontinued immunosuppressive medications, and the prednisone dosage has been tapered to 15 mg/day in 1. Only 2 patients have demonstrated clinical evidence of recurrence of active lupus. One of these patients currently requires no immunosuppressive medication and has a normal performance status. The other patient is currently receiving IV CYC.Conclusion. In patients experiencing the persistence of organ-threatening lupus following standard, aggressive therapy, HSCT may be performed safely, with marked improvement and sustained withdrawal of all immunosuppressive medication for most patients. A phase III randomized trial is warranted to determine the relative efficacy and durability of remission of HSCT compared with standard therapies. Hematopoietic stem cell transplantation (HSCT)is most commonly applied to chemotherapy-sensitive "malignant" hematologic diseases, such as lymphoma or multiple myeloma. These malignancies are characterized by invasive or injurious clonal or oligoclonal lymphocyte proliferation. Diseases for which autologous stem cell transplants are used successfully are believed to be environmentally induced in a setting of genetic susceptibility. HSCT allows for normal, healthy hematopoietic stem cells to repopulate the bone marrow and peripheral blood after chemotherapy-induced elimination of the malignant clones. It may be anticipated that disease-mediating lymphocytes in patients with systemic lupus erythematosus (SLE) should be at least as prone to therapeutic eradication as malignant lymphocytes. If human SLE is also triggered by the hormonal and environmental milieu in a genetically susceptible host, then high-dose chemotherapy and HSCT should also induce sustained lupus-free remissions.

Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus patients with cardiac dysfunction: feasibility and reversibility of ventricular and valvular dysfunction with transplant-induced remission

“…25,26 Subsequently, by avoiding hyper-hydration in patients with underlying cardiac dysfunction or renal impairment, and utilizing bladder irrigation and mesna infusion, we encountered no further episodes of grade III to IV pulmonary edema. 7 Our patients also demonstrated improvement or stability of cardiac function despite exposure to high doses of cyclophosphamide.…”

Stem cell therapy for autoimmune disease: overview of concepts from the Snowbird 2002 tolerance and tissue regeneration meeting

“…SLE is highly responsive to cyclophosphamide, and dose escalation of cyclophosphamide as a conditioning agent has achieved impressive responses. 12 Systemic sclerosis, a disease unresponsive to virtually all therapies, is marginally responsive to cyclophosphamide. Skin scores and quality of life improved to transplant doses of cyclophosphamide.…”

“…11 Yet this same regimen appears highly effective in systemic lupus erythematosus. 12 Whatever the most appropriate concept for a given disease, it is probably prudent to determine outcome with less intense regimens before testing more intense and potentially more toxic conditioning regimens.…”

Development of a phase III trial of hematopoietic stem cell transplantation for systemic lupus erythematosus

“…Although a few patients have relapsed, this regimen has resulted in drug-free, clinical and serologic remission of greater than 4 years. [9][10][11] As presented by Dr Traynor, 34 SLE patients have undergone HSCT at Northwestern University using this regimen with remarkable improvements. Of patients undergoing HSCT, there has been no mortality.…”

“…[1][2][3][4][5][6][7][8] For this group of patients who have failed pulse intravenous cyclophosphamide, autologous hematopoietic stem cell transplanation (HSCT) has induced drug-free, clinical and serologic remission for more than 4 years. [9][10][11] Mobilization and conditioning regimen Mobilization of stem cells from the blood with G-CSF alone has been demonstrated to precipitate a flare of some autoimmune diseases. 12 Before these clinical results were available, concern lingered that proinflammatory cytokines could induce disease exacerbation or reactivation.…”