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Nonmyeloablative Hematopoietic
Stem Cell Transplantation
for Systemic Lupus Erythematosus
Richard K. Burt, MD
Context Manifestations of systemic lupus erythematosus (SLE) may in most pa-
tients be ameliorated with medications that suppress the immune system. Neverthe- less, there remains a subset of SLE patients for whom current strategies are insuffi-cient to control disease.
Objective To assess the safety of intense immunosuppression and autologous he-
matopoietic stem cell support in patients with severe and treatment-refractory SLE.
Design, Setting, and Participants A single-arm trial of 50 patients with SLE re-
fractory to standard immunosuppressive therapies and either organ- or life-threatening visceral involvement. Patients were enrolled from April 1997 through Janu- ary 2005 in an autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) study at a single US medical center.
Interventions Peripheral blood stem cells were mobilized with cyclophosphamide
(2.0 g/m2) and granulocyte colony-stimulating factor (5 µg/kg per day), enriched ex
vivo by CD34ϩ immunoselection, cryopreserved, and reinfused after treatment with cyclophosphamide (200 mg/kg) and equine antithymocyte globulin (90 mg/kg).
Main Outcome Measures The primary end point was survival, both overall and
disease-free. Secondary end points included SLE Disease Activity Index (SLEDAI), se-rology (antinuclear antibody [ANA] and anti–double-stranded (ds) DNA), comple- SYSTEMICLUPUSERYTHEMATO- mentC3andC4,andchangesinrenalandpulmonaryorganfunctionassessedbefore treatment and at 6 months, 12 months, and then yearly for 5 years.
Results Fifty patients were enrolled and underwent stem cell mobilization. Two pa-
tients died after mobilization, one from disseminated mucormycosis and another from sive medications, was generally fatal.
active lupus after postponing the transplantation for 4 months. Forty-eight patients underwent nonmyeloablative HSCT. Treatment-related mortality was 2% (1/50). Byintention to treat, treatment-related mortality was 4% (2/50). With a mean fol- low-up of 29 months (range, 6 months to 7.5 years) for patients undergoing HSCT, overall 5-year survival was 84%, and probability of disease-free survival at 5 years following HSCT was 50%. Secondary analysis demonstrated stabilization of renal func- tion and significant improvement in SLEDAI score, ANA, anti-ds DNA, complement, and carbon monoxide diffusion lung capacity adjusted for hemoglobin.
Conclusions In treatment-refractory SLE, autologous nonmyeloablative HSCT re-
sults in amelioration of disease activity, improvement in serologic markers, and either stabilization or reversal of organ dysfunction. These data are nonrandomized and thus preliminary, providing the foundation and justification for a definitive randomized trial.
ity from active disease, with visceral or- Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00271934
Author Affiliations are listed at the end of this
of Immunotherapy, Northwestern University Fein- For editorial comment see p 559.
berg School of Medicine, 750 N Lake Shore Dr, Chi- Corresponding Author: Richard K. Burt, MD, Division
cago, IL 60611 ([email protected]).
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 1, 2006—Vol 295, No. 5 527
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS participate. All patients had at least 4 of eligibility criteria included World Health Stem Cell Mobilization
and Conditioning
myelitis), vasculitis (confirmed by biopsy abling pain despite narcotic use), ulcer- defined by the Sapporo criteria.18 Nephri- tis required failure of 6 or more monthly visceral organ involvement required fail- daily, 4, 3, and 2 days before transplan- Antibiotic Prophylaxis
Outcome Characteristics
vival and disease remission, which is de- all 50 patients enrolled in the study.
Patient Eligibility
either daily acyclovir or valacyclovir.
dard therapies were enrolled in an autolo- rial Hospital (Chicago, Ill) after signing a n t i b o d y [ A N A ] , a n t i – d o u b l e - approved by an institutional review board 528 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
bin). Statistical significance was set at PϽ.05. Overall and disease-free sur- for 1 year after the transplantation.
yearly thereafter. Medical history, physi- Fluid and Electrolytes
patient was not able to return for follow- Pre-HSCT Patient Demographics
up, medical records and laboratory blood- Fifty patients were enrolled in the trial.
Forty-eight patients underwent HSCT.
local physician or medical facility. If a patient refused or did not complete a test, (range, 6 months to 7.5 years). TABLE 1
vided that he or she participated with the Statistical Analysis
Nonparametric t test analysis using Sta- Pre-HSCT Disease Manifestations
TABLE 2 lists pre-HSCT disease mani-
Anticoagulation Prophylaxis
Table 1. Patient Demographics and Pretransplantation History (N = 50)
For patients receiving anticoagulation or Variable
No. of Patients
anticoagulation was initiated with either Blood Transfusions
Platelet transfusions were given to main- 30 000/µL if patients were receiving an- 1 Patient each: leflunamide, 2-chlorodeoxyadenosine, bin level less than 8.0 g/dL. Platelets and antithymocyte globulin, chlorambucil, gold Abbreviations: LMWH, low-molecular-weight heparin; SLE, systemic lupus erythematosus.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 1, 2006—Vol 295, No. 5 529
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS Table 2. Pretransplantation Disease Manifestations
No. of Patients for Whom Manifestation
Staphylococcus aureus (MRSA) endo- Condition
No. of Patients
Was a Primary Indication for HSCT
edema as a result of volume overload.
ultrafiltration. Thereafter, for patients Abbreviation: HSCT, hematopoietic stem cell transplantation.
of mesna and bladder irrigation with-out hyperhydration. In the last 44 pa- sient ischemic attacks, or transverse my- transplantation was started, for a treat- jiroveci pneumonia on bronchoscopy and related pancytopenia and neutropenia.
Stem Cell Mobilization
Stem cell collection occurred 10 days af- and required a mean of 2.5 apheresis pro- after each dose of cyclophosphamide.
term peritoneal dialysis grew Candida parapsilosis, and blood specimens from active SLE. Three patients without a his- 1 patient grew Candida glabrata. Four pa- 8.95ϫ106 and 5.46ϫ106, respectively.
tients had positive stool-culture results: 3 for Clostridium difficile and 1 for Sal- Toxicity
monella. Cytomegalovirus viremia with- factor VIII deficiency (2 patients) or ITP patients with factor VIII deficiency, the tively (TABLE 3). The mean number of
developed P jiroveci pneumonia and 530 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
Table 3. Transplantation-Related Toxic
Serology and Complement
sion, 1 patient died at 6 months after an was significantly lower (all PϽ.05) at 3, significantly improved (all PϽ.05) at 3, cantly improved (all PϽ.05) at 3, 6, 12, (FIGURE 2). C4 also improved in par-
curred in patients entering remission.
patient was placed in hospice for refrac- Disease Activity
and Organ Function
combinations of fever, rash,arthralgia, transient tachycardia, significantly lower (all PϽ.05) for up to 5 years after HSCT (FIGURE 3). Pul-
5-year survival was 84% (FIGURE 1).
Abbreviations: ANC, absolute neutrophil count; ATG, anti- thymocyte globulin; HSC, hematopoietic stem cell; HSCT,HSC transplantation.
or renal failure. Of the 25 patients with a history of nephritis (TABLE 4), 3 were
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 1, 2006—Vol 295, No. 5 531
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS Figure 1. Probability of Survival and Relapse in Lupus Patients Undergoing Hematopoietic
phritis; that patient’s renal functionrecovered, and the patient has subse- received an aminoglycoside duringHSCT and never became independent of dialysis. Four patients with pretrans- quently became dialysis dependent(Table 4) because of exposure to dye Figure 2. Serology and Complement Before and After Hematopoietic Stem Cell Transplantation
ANA indicates antinuclear antibody; anti-ds, anti–double-stranded. Blue bars indicate median values.
Figure 3. SLE Disease Activity Index (SLEDAI) and Carbon Monoxide Diffusion Lung Capacity (DLCO) Corrected for Hemoglobin Before and
After Hematopoietic Stem Cell Transplantation
532 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS a result of patient selection, the condi- ment renal biopsies were not obtained.
lapse, and 1 never entered remission.
Similarly, 5 patients had AIHA: 3 are Table 4. Renal Outcome in the Subset of Patients With a History of Pre-HSCT Nephritis
Most Recent
Patients With
Post-HSCT Creatinine
Pre-HSCT Nephritis
Clearance, mL/min
Clearance, mL/min
Current Status*
never achieved remission, respectively.
anticoagulation was not standardized.
ability of disease-free survival at 5 years Abbreviations: ESRF, end-stage renal failure; HSCT, hematopoietic stem cell transplantation; NA, not applicable; SLE, *Remission is defined by Responder Index for Lupus Erythematosus criteria, as described in the text.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 1, 2006—Vol 295, No. 5 533
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS contrast to eligibility criteria for malig- contraindication for transplantation, on- often the indication for stem cell trans- electrolyte abnormalities, if given hyper- considered an SLE-related eligibility cri- terion for transplantation, is a contrain- to a prolonged corticosteroid taper.
p e r i o d b e f o r e e n r o l l m e n t , a n d major indication for transplantation.
function, a significant percentage of lu- active inflammation, vasculitis, and APS.
tinely monitor or treat CMV viremia.
preemptive antimicrobial prophylaxis.
534 JAMA, February 1, 2006—Vol 295, No. 5 (Reprinted)
2006 American Medical Association. All rights reserved.
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS the integrity of the data and the accuracy of the dataanalysis.
Study concept and design: Burt, Traynor, Rosa, less, this trial demonstrates that within Acquisition of data: Burt, Traynor, Statkute, Barr, Rosa,Verda, Krosnjar, Quigley, Yaung, Villa, Takahashi, Analysis and interpretation of data: Burt, Traynor,Statkute, Jonanovic, Oyama.
Drafting of the manuscript: Burt, Traynor, Rosa, Verda, Krosnjar, Quigley, Yaung, Villa, Takahashi, Oyama.
Critical revision of the manuscript for important in-tellectual content: Burt, Traynor, Statkute, Barr, Statistical analysis: Verda, Takahashi, Jonanovic.
Obtained funding: Burt.
Author Affiliations: Division of Immunotherapy (Drs
Administrative, technical, or material support: Burt, Rosa, Burt, Traynor, Statkute, Verda, Krosnjar, Takahashi, Schroeder, Krosnjar, Quigley, Yaung, Villa, Takahashi.
and Oyama, Mss Quigley and Yaung, and Mr Villa), Study supervision: Burt, Traynor, Statkute, Oyama.
Division of Rheumatology (Drs Barr and Schroeder), Financial Disclosures: None reported.
Division of Nephrology (Dr Rosa), and Department of Funding/Support: We wish to thank the BraveWings
Preventive Medicine (Dr Jonanovic), Department of Foundation and Ginger’s Tomorrow Foundation for Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill. Dr Traynor is now with the Role of the Sponsor: The funding organizations had
Division of Hematology/Oncology, University of Mas- no role in the design or conduct of the study; collec- tion, management, analysis, or interpretation of the Author Contributions: Dr Burt had full access to all
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