High-Dose Cyclophosphamide and Stem Cell Transplantation for Refractory Systemic Lupus Erythematosus

Systemic lupus erythematosus is a devastating systemic autoimmune disease that predominantly affects young women, is more common in African-Americans than in whites, and results in poor quality of life. Lupus has no cure, and up to 90% of patients require corticosteroids for disease control.¹ More than half of patients with lupus have permanent organ damage, much of which is either directly due to or increased by corticosteroids.¹ Mortality is increased in patients with systemic lupus erythematosus, with accelerated atherosclerosis the most important contributing factor,² although the risk of cancer is also increased.³

There have been no new US Food and Drug Administration-approved drugs or biologic treatments for systemic lupus erythematosus in many decades. The criterion standard treatment for severe organ-threatening lupus (renal lupus, central nervous system lupus) is monthly intravenous cyclophosphamide (500–1000 mg/m²) for a 6-month induction period, followed by quarterly intravenous cyclophosphamide as a maintenance regimen for another 2 years.⁴ Intravenous cyclophosphamide causes immediate toxicity in terms of fatigue, nausea, vomiting, alopecia, cytopenias, infection, and hemorrhagic cystitis as well as late toxicity, in terms of cancer (lymphoma, skin cancer, bladder cancer), myelodysplastic syndrome, and premature ovarian failure.⁵

These long-term toxicities may be acceptable if cyclophosphamide was curative. However, in a recent trial of patients with lupus nephritis, a 6-month cyclophosphamide induction regimen led to complete responses in only 5.8% of cases.⁶ Progressive renal damage occurs in about 25% of patients with lupus nephritis despite use of intravenous cyclophosphamide or other therapies.⁷ This has led to attempts to find alternative cyclophosphamide regimens. For example, in the Euro-Lupus Nephritis trial, a lower dosage of cyclophosphamide, given more often (every 2 weeks) had equal efficacy as the 500 to 1000 mg/m²-monthly regimen, but with less toxicity.⁸

For patients with severe lupus, use of a high-dose “immunoblative” cyclophosphamide regimen (200 mg/kg) alone or with stem cell “rescue” therapy has been investigated. High-dose cyclophosphamide without stem cell rescue was initially used to treat severe aplastic anemia, another life-threatening autoimmune disease.⁹ With this regimen, lymphocytes are destroyed but bone marrow stem cells are spared, allowing a “re-booting” of a naïve immune system. Among 14 patients with severe lupus who received high-dose immunoblative cyclophosphamide as part of an open-label series conducted by our research group, about 40% of patients had a durable complete remission.¹⁰ Perhaps surprisingly, clinical improvement during the initial period of profound immunosuppression was not the rule; instead, slow, steady improvement over several months occurred.¹⁰ Initial results using this regimen for other autoimmune diseases also have been promising.^{11 - 13}

In a phase 1 study investigating high-dose chemotherapy combined with autologous hematopoetic stem cell transplantation, with the hope of shortening the 10 to 14-day period of aplasia that occurs after high-dose cyclophosphamide therapy, Traynor et al¹⁴ mobilized and collected stem cells from patients with severe lupus before giving high-dose cyclophosphamide and then re-infused the stem cells 2 days after the completion of the chemotherapy. At a median follow-up of 25 months, all 7 patients who received high-dose chemotherapy and stem cell infusion were free of signs of active lupus. In a follow-up report that included 15 patients with severe lupus, 7 of whom were critically ill, 83% showed complete remission at a median follow-up of 36 months.¹⁵ In a report of 53 patients from a European registry, high-dose chemotherapy followed by peripheral stem cell transplantation was associated with remission of disease activity in 66% of patients at 6 months follow-up; however, 32% of these patients with remission subsequently relapsed and 12 deaths occurred within 1.5 months after the procedure.¹⁶

In this issue of JAMA, Burt and colleagues¹⁷ report the long-term follow-up of their expanded open label series. This single arm nonrandomized study includes 50 patients with severe lupus that was refractory to standard immunosuppressive therapies and who had either organ- or life-threatening visceral involvement. The use of intense immune suppression and autologous nonmyeloablative hematopoetic stem cell transplantation resulted in significant amelioration of disease activity. With a median follow-up of 29 months (range, 6 months-7.5 years), overall survival was 84% and the probability of 5-year disease-free survival (prednisone dose of less than 10 mg/d and no immunosuppressive medications) was 50%. Although a more strict definition would include no clinical disease activity using a clinical disease activity index such as RIFLE¹⁸ or BILAG,¹⁹ Burt et al¹⁷ report that secondary outcomes (serological studies, complement levels, and renal function) and a validated disease activity index (SLEDAI) all demonstrated clinically meaningful improvement.

Even though these data suggest that high-dose cyclophosphamide and administering peripheral blood stem cells may provide benefit in severe refractory lupus, this approach also may have drawbacks. Mobilization of peripheral stem cells is associated with severe cytopenias and may increase morbidity and mortality of the procedure. In the study by Burt et al,¹⁷ 4 patients (8%) developed bacteremia during stem cell mobilization and 1 patient died a week after stem cell mobilization, but before starting stem cell transplantation (treatment-related mortality of 2%). In addition, while the duration of neutropenia appears to be reduced with the autologous stem cell transplantation regimen (ie, 2-3 days shorter in the study by Burt et al¹⁷ ), the number of red cell and platelet transfusions was increased compared with the lupus treatment regimen without stem cell transplantation. In addition, mobilization of stem cells theoretically may increase the risk of relapse through re-infusion of contaminating lymphocytes in the stem cell autograft, and also increases the cost of the procedure more than 2-fold.

The original hope of stem cell transplanatation was “going for the cure” in patients with severe lupus. The remission rates reported with use of high-dose cyclophosphamide with stem cell transplantation, as reported by Burt et al,¹⁷ or without autologous stem cells,¹⁰ do not necessarily represent “cure”. Many patients continue to have lupus autoantibodies and with long-term follow-up, some patients with initial complete remissions will have late relapses. However, in these studies therapy was given as a “salvage regimen” to patients with lupus who had failed or were refractory to multiple other therapies. Thus, as in the report by Burt et al,¹⁷ the therapy offered substantial benefit–with either partial or complete response–to the majority of patients.

The current research climate in systemic lupus erythematosus is rich in potential new therapies, including a recent trial showing a significantly higher complete response rate of mycophenolate mofetil over monthly intravenous cyclophosphamide in patients with renal lupus⁶ and benefit reported in 2 open-label series of patients treated with rituximab.^{20 - 21} The toxicity of high-dose cyclophosphamide, including the potential for death from infection, always must be balanced against the benefit and risk of these other potential therapies. The study by Burt et al¹⁷ confirms that intense immune suppression with high-dose cyclophosphamide therapy along with autologous hematopoetic stem cell transplantation has benefit in patients with severe refractory lupus. Whether this approach represents a definitive advance over more conventional immunosuppressive therapies will need to be answered in randomized controlled trials.