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リウマチ Vol.41 No.2 indexに戻る
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リウマチ Vol.41 No.2 |
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「Haematopoietic Stem Cell Transplantation（HSCT）for
Severe Autoimmune Disease：An Update of Results and Planned Trials」 |
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| Alan Tyndall |
| Dept. of Rheumatology, Univ. Hospital Basel,
Switzerland |
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| 招請講演 |
Reporting on behalf of the EULAR,
the EBMT and the International Data Base in Basel/Switzerland there
are currently（end of September,
2000）324 registrations of HSCT performed for treatment of severe
autoimmune disease（AD), 314 autologous and 5 allogeneic. Data is
from 71 centres in 22 countries, with a median follow-up of 12 months（3-55).
ADs treated are：Multiple sclerosis（MS）95 cases, scleroderma（Ssc）66
cases, Rheumatoid arthritis（RA）41 cases, JIA 35 cases, Systemic lupus
erythematodes（SLE）23 cases, ITP 7 cases, Cryoglobulinaemia 4 cases,
Polymyositis/dermatomyositis 5 cases, Wegeners granulomatosis 3,
Bechets disease 3 and others.
An overall transplant related mortality（TRM）of 9％（actuarially adjusted
at 12 months）was seen, with inter-disease differences（12.5％ in SSc
and 6％ in RA）reflecting differing vital organ involvement at the
time of transplant. The overall TMR is coming down, being 12％ before
1998, 10％ in 1999 and 4％ in 2000.
Most patients received a peripheral HSCT mobilised with cyclophosphamide（Cy）and
G-CSF, following conditioning with one of four basic regimens（BEAM±ATG,
Cy alone, Cy plus radiation or Busulphan plus cyclophosphamide. Most
graft products were T cell depleted ex-vivo using CD34 selection±T
and B cell purging.
Around 2/3 of patients stabilised or improved following HSCT, with
some relapses seen, especially in RA（around 50％, but more easily
controlled than pre-transplant). In scleroderma, 70％ achieved a 25％
or better improvement in skin score, with a trend to stabilisation
of the lung function. Excluding patients with the current criteria,
the TRM would be 7.5％. Results for the other ADs will be presented.
Standardised international（EBMT and IBMTR）outcome measurement forms
at set time points pre and post transplant have been developed for
the major ADs（SSc, MS, RA, JIA and SLE).
Some patients improved following Cy 4g/m↑2↑ given for mobilisation
only, and did not proceed to transplant. Others suffered severe,
sometimes fatal complications of mobilisation, either organ toxicity
from the drugs or G-CSF associated AD flare. No clear advantage of
more severe conditioning regimens was seen, nor a clearly increased
relapse rate in patients receiving non selected（purged）grafts. Prospective,
randomised controlled trials are needed and being planned to establish
the place of HSCT in severe AD treatment.
Such a protocol is available for SSc（the ASTIS Trial）and interested
centres are invited to participate. Details at：www.astistrial.com
or astistrial-fps＠unibas.ch. Essentially, HSCT（mobilization Cy 4g/m↑2↑
and G-CSF, conditioning Cy 200mg/kg and ATG with CD34 selection）will
be compared with Cy 750mg/m↑2↑ given monthly over 12 months. The
primary end point is event free survival.
An RA protocol is being written, mobilization with Cy 4g/m↑2↑ then
randomised to either HSCT（Cy 200mg/kg）or further best available therapy.
No CD34 selection or T-cell purging is planned given the lack of
benefit in phase I and II trials.
For MS, HSCT（BEAM and ATG）will be compared with either interferon
beta or mitoxanthrone, to be decided by a writing committee.
References：
Marmont A, Gratwohl A, Vischer T and Tyndall A. Haematopoietic precursor
cell transplantation for autoimmune disease（letter). Lancet 1995,
345：978
Tyndall A and Gratwohl A. Leader. Haematopoietic stem and progenitor
cells in the treatment of severe autoimmune diseases. Ann Rheum Dis
1996；55：149-151
Fassas A, Anagnostopoulos A, Kazis A et al. Autologous stem cell
transplantation in progressive multiple sclerosis-an interim analysis
of efficacy. J Clin Immunol 2000；(Suppl 1)：24-30
McSweeney P,, Furst D, West S. High dose immunosuppressive therapy
for rheumatoid arthritis：some answers and more questions. Arthritis
Rheum 1999；42：2269-2274
Burt R, Traynor A, Pope R et al. Treatment of autoimmune disease
by intensive immunosuppressive conditioning and autologous hematopoietic
stem cell transplantation. Blood 1998；10：3505-3514
Wulffraat N, Van Royan A, Bierings M, Vossen J, Kuis W. Autologous
haematopoietic stem-cell transplantation in four patients with refractory
juvenile chronic arthritis. Lancet 1999；353：550-553
Tyndall A, Fassas A, Passweg J et al. Autologous haematopoietic stem
cell transplants for autoimmune diseases：feasibility and transplant-related
mortality. Bone Marrow Transplant 1999；24：729-734
Advances in targeted therapies：TNF alpha blockade in clinical practice.
Ann Rheum Dis 1999(suppl 1)；I1-130
Bryan C, Knight C, Black CM and Silman A. Prediction of five year
survival following presentation with scleroderma：development of a
simple model using three disease factors at first visit. Arthritis
Rheum 1999；42：2660-2665
Binks M, Passweg J, Furst D et al. Improved skin score etc（Ann Rheum
Dis 2000（in press)）
Traynor AE, Schroeder J, Rosa RMet al. Treatment of severe sytemic
lupus erythematosus with high dose chemotherapy and haemopoietic
stem-cell transplantation：a phase I study. Lancet 2000；356：701-707
Openshaw H, Stuve O, Antel JP et al. Multiple sclerosis flares associated
with recombinant granulocyte-stimulating factor. Neurology 2000；54：2147-50
Tyndall A and Gratwohl A. Blood and marrow stem cell transplants
in autoimmune disease：a consensus report written on behalf of the
European League Against Rheumatism（EULAR）and the European Group for
Blood and Marrow Transplantation（EBMT), Bone Marrow Transplant 1997；19：643-645
Kashyap A, Passweg J, Tyndall A. Autologous hematopoietic stem cell
transplant conditioning regimens for the treatment of severe autoimmune
diseases（In press-Autologous Blood and Marrow Transplantation 2000,
ed K Dicke and A Keating：proceedings of the tenth International Symposium,
Arlington, Texas, July 2000
Rolink AG, Melchers F. Precursor B cells from Pax-5 deficient mice-stem
cells for macrophages, granulocytes, osteoclasts, dendritic cells,
natural killer cells, thymocytes and lymphocytes. Curr Top Microbiol
Immunol 2000；251：21-26
Guillaume T, Rubinstein DB, Symann M. Review Immune reconstitution
and immunotherapy after autologous hematopoietic stem cell transplantation.
Blood. 1998；92(5)：1471-90. |
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