Www2.dti.ufv.br

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 (rburt@northwestern.edu).
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.
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS Follow-up
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.
HEMATOPOIETIC STEM CELL TRANSPLANTATION IN LUPUS Overall and Disease-Free Survival
Table 3. Transplantation-Related Toxic
Variable
Patients
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
Pre-HSCT
Most Recent
Patients With
Creatinine
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
data; or in the preparation, review, or approval of the of the data in the study and takes responsibility for REFERENCES
1. Abu-Shakra M, Urowitz MB, Gladman DD, Gough
14. Burt RK, Traynor A, Ramsey-Goldman R. Hema-
25. Young N, Speck B. Antithymocyte and antilym-
J. Mortality studies in systemic lupus erythematosus: topoietic stem cell transplantation for systemic lupus phocyte globulins: clinical trials and mechanism of results from a single center, II: predictor variables for erythematosus. N Engl J Med. 1997;337:1777-1778.
action. Prog Clin Biol Res. 1984;148:221-226.
mortality. J Rheumatol. 1995;22:1265-1267.
15. Burt RK, Traynor AE, Pope R, et al. Treatment of
26. Kang I, Park SH. Infectious complications in SLE
2. Cervera R, Khamashta MA, Font J, et al. Morbidity
autoimmune disease by intense immunosuppressive after immunosuppressive therapies. Curr Opin and mortality in systemic lupus erythematosus during conditioning and autologous hematopoietic stem cell a 5-year period: a multicenter prospective study of 1,000 transplantation. Blood. 1998;92:3505-3514.
27. Salzberger B, Bowden RA, Hackman RC, Davis C,
patients: European Working Party on Systemic Lupus 16. Traynor AE, Schroeder J, Rosa RM, et al. Treat-
Boeckh M. Neutropenia in allogeneic marrow trans- Erythematosus. Medicine. 1999;78:167-175.
ment of severe systemic lupus erythematosus with plant recipients receiving ganciclovir for prevention of 3. Austin HA III, Klippel JH, Balow JE, et al. Therapy
high-dose chemotherapy and haemopoietic stem- cytomegalovirus disease: risk factors and outcome.
of lupus nephritis: controlled trial of prednisone and cell transplantation: a phase I study. Lancet. 2000;356: cytotoxic drugs. N Engl J Med. 1986;314:614-619.
28. Euler HH, Harten P, Zeuner RA, Schwab UM. Re-
4. Bansal VK, Beto JA. Treatment of lupus nephritis:
17. Traynor AE, Barr WG, Rosa RM, et al. Hemato-
combinant human granulocyte colony stimulating fac- a meta-analysis of clinical trials. Am J Kidney Dis. 1997; poietic stem cell transplantation for severe and refrac- tor in patients with systemic lupus erythematosus as- tory lupus: analysis after five years and fifteen patients.
sociated neutropenia and refractory infections.
5. Chan TM, Li FK, Tang CS, et al; Hong Kong-
Arthritis Rheum. 2002;46:2917-2923.
J Rheumatol. 1997;24:2153-2157.
Guangzhou Nephrology Study Group. Efficacy of 18. Wilson WA, Gharavi AE, Koike T, et al. Interna-
29. Zavala F, Masson A, Hadaya K, et al. Granulocyte-
mycophenolate mofetil in patients with diffuse pro- tional consensus statement on preliminary classifica- colony stimulating factor treatment of lupus autoim- liferative lupus nephritis. N Engl J Med. 2000;343: tion criteria for definite antiphospholipid syndrome: mune disease in MRL-lpr/lpr mice. J Immunol. 1999; report of an international workshop. Arthritis Rheum.
6. Takada K, Illei GG, Boumpas DT. Cyclophospha-
30. Gottenberg JE, Roux S, Desmoulins F, Clerc D, Ma-
mide for the treatment of systemic lupus erythema- 19. American College of Rheumatology Ad Hoc Com-
riette X. Granulocyte colony-stimulating factor therapy tosus. Lupus. 2001;10:154-161.
mittee on Systemic Lupus Erythematosus Response resulting in a flare of systemic lupus erythematosus: 7. Esdaile JM. Prognosis in systemic lupus erythema-
Criteria. The American College of Rheumatology re- comment on the article by Yang and Hamilton. Ar- tosus. Springer Semin Immunopathol. 1994;16:337-355.
sponse criteria for systemic lupus erythematosus clini- thritis Rheum. 2001;44:2458-2460.
8. Goldblatt F, Isenberg DA. New therapies for sys-
cal trials: measures of overall disease activity. Arthri- 31. Mills JA. Systemic lupus erythematosus. N Engl J
temic lupus erythematosus. Clin Exp Immunol. 2005; tis Rheum. 2004;50:3418-3426.
20. Bombardier C, Gladman DD, Urowitz MB, Caron
32. Leandro MJ, Edwards JC, Cambridge G, Ehren-
9. Burt RK, Verda L, Oyama Y, Statkute L, Slavin S.
D, Chang CH. Derivation of the SLEDAI: a disease ac- stein MR, Isenberg DA. An open study of B lympho- Non-myeloablative stem cell transplantation for au- tivity index for lupus patients. Arthritis Rheum. 1992; cyte depletion in systemic lupus erythematosus. Ar- toimmune diseases. Springer Semin Immunopathol.
thritis Rheum. 2002;46:2673-2677.
21. Statkute L, Traynor A, Oyama Y, et al. Antiphos-
33. Eisenberg R. SLE: rituximab in lupus. Arthritis Res
10. Ikehara S, Good RA, Nakamura T, et al. Ratio-
pholipid syndrome in patients with systemic lupus ery- nale for bone marrow transplantation in the treat- thematosus treated by autologous hematopoietic stem 34. Anolik JH, Barnard J, Cappione A, et al. Ritux-
ment of autoimmune diseases. Proc Natl Acad Sci U cell transplantation. Blood. 2005;106:2700-2709.
imab improves peripheral B cell abnormalities in hu- 22. Jayne D, Passweg J, Marmont A, et al. Autolo-
man systemic lupus erythematosus. Arthritis Rheum.
11. Snowden JA, Brooks PM, Biggs JC. Haemopoi-
gous stem cell transplantation for systemic lupus etic stem cell transplantation for autoimmune diseases.
erythematosis. Lupus. 2004;13:168-176.
35. Willis F, Marsh JC, Bevan DH, et al. The effect
23. Loberiza FR Jr, Zhang MJ, Lee SJ, et al. Associa-
of treatment with Campath-1H in patients with 12. Burt RK, Slavin S, Burns W, Marmont A. Induc-
tion of transplant center and physician factors on mor- autoimmune cytopenias. Br J Haematol. 2001; tion of tolerance in autoimmune diseases by hema- tality after hematopoietic stem cell transplantation in topoietic stem cell transplantation. Blood. 2002;99:768- the United States. Blood. 2005;105:2979-2987.
36. Cohen Y, Polliack A, Nagler A. Treatment of re-
24. Dubey S, Nityanand S. Involvement of Fas and
fractory autoimmune diseases with ablative immuno- 13. Marmont AM. Stem cell transplantation for se-
TNF pathways in the induction of apoptosis of T cells therapy using monoclonal antibodies and/or high dose vere autoimmune diseases: progress and problems.
by antithymocyte globulin. Ann Hematol. 2003; chemotherapy with hematopoietic stem cell support.
Haematologica. 1998;83:733-743.
Curr Pharm Des. 2003;9:279-288.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, February 1, 2006—Vol 295, No. 5 535

Source: https://www2.dti.ufv.br/noticia/files/anexos/phpD6o4Wg_5654.pdf