Autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) ameliorates disease activity, improves serologic markers, and stabilizes or reverses organ dysfunction in about half of patients with treatment refractory systemic lupus erythematosus (SLE), according to a preliminary open-label study published in the February 1 issue of the Journal of the American Medical Association.1
 
In the single-arm study of 50 treatment-refractory SLE patients, 48 patients underwent HSCT (two patients died before transplantation), with an average follow-up of about 2.5 years. The researchers reported that 84% of patients undergoing HSCT had an overall 5-year survival rate, and 50% had a probability of disease-free survival of 5 years. The longest continuous duration of remission has been 7.5 years, according to the data.

The trial also reported that 2% (1/50) of participants had a treatment-related fatality and a 4% (2/50) fatality rate, based on an intention-to-treat analysis. Specifically, one death occurred from disseminated mucormycosis presenting 1 week after stem-cell mobilization, but before transplantation, and the second death occurred after transplantation was postponed for 4 months. Another patient developed Pneumocystis jiroveci pneumonia after mobilization, and 4 patients developed gram-positive bacteremia during mobilization. Additionally, 14 patients developed bacteremia during transplantation, the study showed.

Justification for randomized controlled study

The study authors note that despite reductions in SLE-related mortality in the latter part of the 20th century—due to improved supportive care and more aggressive use of immunosuppressive agents such as monthly intravenous-pulse cyclophosphamide or mycophenolate mofetil—significant morbidity and mortality from active disease and visceral organ involvement persist.

"This trial provides the justification for a randomized study that compares autologous HSCT with continued standard of care," conclude the researchers, led by Richard K. Burt, MD, of the division of immunotherapy at Northwestern University's Feinberg School of Medicine in Chicago, Illinois. "Continuing failing therapy for such patients is problematic but necessary to confirm that the increased acute risk of HSCT would be offset by better disease control and improved long-term survival, especially because the standard of care for lupus is constantly changing with the introduction of newer therapeutic agents."

As part of the trial design, peripheral blood cells were mobilized with 2.0 g/m2 of cyclophosphamide and granulocyte colony-stimulating factor at 5 mg/kg per day. They were enriched ex vivo by CD34+ immunoselection, frozen, and then reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (ATG: 90 mg/kg). The protocol used in this study was designed 10 years ago, but future protocols may consider replacing equine ATG with rabbit ATG, rituximab, or alemtuzumab.

HSCT not a cure for lupus

In an editorial accompanying the new study,2 Michelle Petri, MD, MPH, and Robert Brodsky, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, point out that the HSCT regimen used in the new study did result in a significant amelioration of SLE disease activity and improvements in secondary outcomes including complement levels, serologic activity, renal function, and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

However, the authors write, HSCT may have drawbacks—specifically, the morbidity and mortality of the procedure. Moreover, "the original hope of stem-cell transplantation was ‘going for the cure' in patients with severe lupus," Drs. Petri and Brodsky say. "The remission rates reported with use of high-dose cyclophosphamide with stem-cell transplantation, as reported by Burt et al,1 or without autologous stem cells, do not necessarily represent ‘cure'."

For example, 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 had been refractory to multiple other therapies. Thus, as in the report by Burt et al, the therapy offered substantial benefit—with either partial or complete response—to the majority of patients," Drs. Petri and Brodsky explain. They conclude that randomized controlled trials are necessary to determine whether this approach is a definitive advance over conventional immunosuppressive therapy.

HSCT appears promising as therapeutic approach for SLE

"These are very promising, mature data and point toward the fact that a major clinical benefit is achieved in at least one-third of severe SLE patients who failed standard therapies, since so many can get completely off immunosuppression for a prolonged time," says Steven Pavletic, MD, head of the Graft-versus-Host and Autoimmunity Unit of the Experimental Transplantation and Immunology Branch at the National Cancer Institute in Bethesda, Maryland. "Transplantation for lupus is a reality and the field has been active for about 10 years now, with steady improvements in regimen safety, as this study demonstrates."

However, Dr. Pavletic points out, these data originate from the first-generation studies, which were not designed with rigorously defined entry and response criteria. Instead, the purpose was to prove safety and feasibility and assess the therapeutic promise of such an approach.

"This study and other recent studies of immune reconstitution after autologous transplantation definitively support the notion of the curative potential of such treatments for autoimmune diseases after development of even more effective and better-designed protocols," Dr. Pavletic tells CIAOMed. Now, "we are waiting for the results of the second-generation trials that are more rigorously designed [and] more thoroughly look into the remission quality and biology of the disease, and above all, that use potentially more effective strategies."

References

  1. Burt RK, Traynor A, Statkute L, et al. Nonmyeloablative hematopoietic stem cell tansplantation for systemic lupus erythematosus. JAMA. 2006;295:527-535.
  2. Petri M, Brodsky R. High-dose cyclophosphamide and stem cell transplantation for refractory systemic lupus erythematosus. JAMA. 2006;295:559-560.