current status and future prospectives

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Artigo Especial / Special Article
Hematopoietic stem cell transplantation for autoimmune
diseases in Brazil: current status and future prospectives
Júlio C. Voltarelli
In this paper, we discuss the launching of a cooperative protocol of
hematopoietic stem cell transplantation for autoimmune diseases in Brazil. We
present specific conditions of the country's health system which would affect the
trial, preliminary results of the first nine patients transplanted under the
protocol (4 systemic lupus, 3 multiple sclerosis, one systemic sclerosis and one
overlapping lupus + systemic sclerosis) and future prospectives of organizing
phase III randomized trials to answer specific scientific questions pending in the
field.
Keywords: Hematopoietic stem cell transplantation, autoimmune diseases,
autologous transplantation, systemic lupus erythematosus, multiple sclerosis,
systemic sclerosis
Introduction
Application of hematopoietic stem cell transplantation (HSCT) for treatment of systemic
autoimmune diseases (AID) in developing countries requires consideration of peculiar
aspects of the diseases and of the health system in those countries. In regards particularly to
Brazil, some aspects to be considered are the following: a) A very large experience
transplanting hematologic autoimmune diseases, such as acquired aplastic anemia, including
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devising of new conditioning regimens for hypertransfused/presensitized patients (Medeiros
et al, 1998) (1), b) Anecdotical cases of systemic autoimmune diseases submitted to
autologous HSCT since 1996 with favorable results (Ferreira et al, 1996, see Table 4) (2), c)
Probably a worse activity and prognosis of severe autoimmune diseases in the patient
population treated with conventional therapy due in part to poor economical and social
conditions (Table 1), (Johnson et al, 1994) (3), d) High prevalence of tropical autoimmune
diseases such as rheumatic fever and some forms of pemphigus, e) Difficult access to new
technologies (stem cell selection columns, monoclonal antibodies) and therapies (anti-TNF
agents), which impairs our capacity to deliver the best medical treatment to the patients and
to participate in international cooperative trials, f) Universal coverage of health care by the
state, but in a highly regulated fashion for high cost therapies such as HSCT, g) Large
availability of HLA-identical donors (>50%) in the general population due to the big size of
families (Table 2), (Voltarelli & Stracieri, 2000) (4).
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Current status of hsct for aid in Brazil
In October 2000, we organized a meeting in Ribeirão Preto, Brazil to discuss strategies to
implement a program of HSCT for autoimmune diseases in the country. International experts
from USA (R. Burt, D. Patel, W. Burns) and Europe (R. Arnold) met with representatives of
main BMT/Rheumatology/Neurology Brazilian groups and it was decided to start a pilot,
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phase I/II national cooperative study of autologous transplantation for refractory systemic
lupus erythematosus (SLE), systemic sclerosis (SS) and multiple sclerosis (MS).
Mobilization of HSC is performed with cyclophosphamide (2 g/m2) plus G-CSF (10 µg/kg/d)
and conditioning is CY + ATG for SLE, BEAM + ATG for MS and CY + Fludarabine +
ATG for SS. Horse ATG is given at 15 mg/kg (3 doses before stem cell infusion and 3 doses
after infusion) to replace in vitro T cell depletion/SC selection (Table 3). Conditioning for
SLE and MS followed standard protocols used elsewhere (5, 6), while for SS a highly
immunosuppressive combination was adapted from mini-allo transplants (7). The program
started in June 2001 and 9 transplants have been performed under the protocol (4 for SLE, 3
for MS, 1 for systemic sclerosis and 1 for an overlapping syndrome of SLE + SS) in three
centers (Table 4) and other centers are obtaining IRB approval and accruing patients to be
engaged in the protocol. Preliminary results show beneficial effects in most patients and an
initial significant morbidity/mortality of the transplant procedure due to specific problems of
the patient group (kidney failure and fluid overload in lupus nephritis, disease flare in
systemic sclerosis and high toxicity in advanced multiple sclerosis). These problems certainly
will be overcome with a better patient selection and acquisition of more experience by the
centers in managing special transplant related complications in autoimmune patients.
Main obstacles for the development of the program are the competition for beds in the
existing BMT Units and the difficult interaction between transplant and autoimmune
professionals to work up the logistics of the protocol. On the other hand, there is great
interest and pressure of the patient population to speed the transplant program.
Future Prospectives
After the various centers activate their protocols and gain experience with this new type of
transplant, we plan to start randomized prospective trials in order to choose the best modality
of treatment for each disease. Possibilities of randomization that are under consideration are:
1) Positive selection of CD34 stem cells x unmanipulated transplants, 2) ATG x CAMPATH
for in vivo T cell depletion, 3) TBI or busulfan based conditioning regimens x standard
regimens, 4) Transplantation x best conventional treatment (White et al, 2000) (8), as started
in Europe with the ASTIS trial for systemic sclerosis, 5) Autologous x mini-allo transplants.
This latter randomization could be done on a biological basis (between patients with and
without an HLA identical donor), two groups that are at least split in approximately 50:50%
in Brazil, as mentioned earlier (Table 3). In the above mentioned Symposium, it was decided
that a randomization based on the infusion (or not) of autologous stem cells (Brodsky &
Smith, 1999) (9) would be too risky for the patients without stem cell support.
Insertion of Brazilian groups into international phase III trials currently planned/launched in
Europe/USA, comparing transplant and conventional strategies, depends on the results of our
pilot studies, encouraging referral of early stage patients, and availability of resources needed
for those trials (stem cell selection columns, monoclonal antibodies, anti-TNF agents for
rheumatoid arthritis patients, etc). Alternatively, we may run our own trials, to answer
questions relevant to our specific conditions, such as the need of in vitro manipulation of
cells, or start pilot trials for diseases not transplanted in developed countries, such as
diabetes, pemphigus and pulmonary interstitial fibrosis. Thus, even with less resources than
the First World countries, we can give a significant contribution to the field, like that shown
by Fassas et al (10) in Greece for multiple sclerosis and by groups in China for systemic
lupus erythematosus (11, 12). Finally, in developing countries, one-shot therapy like HSCT is
usually cheaper and have a better cost-benefit ratio than prolonged immunosuppression
required to control severe autoimmune diseases, making transplantation a good candidate for
becoming the therapy of choice for many forms of those diseases in near future in Brazil.
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Acnowledgments
This work is supported by FAPESP-CEPID, FAEPA-HCFMRP-USP, FUNDHERP and
CNPq.
O transplante de células precursoras hematopoéticas em doenças autoimunes no
Brasil: estado atual e perspectivas
Resumo
Neste trabalho, discutimos a implantação de um protocolo cooperativo de transplante de
células tronco hematopoéticas para doenças auto-imunes no Brasil. Apresentamos as
condições específicas do sistema de saúde do país que poderiam afetar o projeto, resultados
preliminares dos primeiros nove pacientes transplantados (quatro com lúpus sistêmico, três
com esclerose múltipla, um com esclerose sistêmica e um com superposição de lúpus com
esclerose sistêmica) e perspectivas futuras de organização de estudos randomizados de fase
III para responder questões específicas pendentes nesta área.
Palavras-chave: Transplante de células tronco hematopoéticas, transplante autólogo,
doenças auto-imunes, lúpus eritematoso sistêmico, esclerose múltipla, esclerose sistêmica
References
1. Medeiros CR, Bitencourt MA, Zanis-Neto, J, Pasquini R. Busulfan and cyclophosphamide
(Bu + Cy) as conditioning regimen to transfused patients (pts) younger than 20 years old
treated with bone marrow transplantation. Blood 1998; 92: 135a.
2. Ferreira E, Ribeiro A, Bacal NS et al. Transplante de células tronco periféricas autólogas
no tratamento de doença auto-imune: Remissão completa da anemia hemolítica por
aglutininas a frio e concomitante vasculite. Bol. Soc. Bras. Hematol. Hemoter., 18 (supl):
191-0.
3. Johnson AE, Cavalcanti FS, Gordon C, et al. Cross-sectional analysis of differences
between patients with systemic lupus erythematosus in England, Brazil and Sweden. Lupus
1994; 3: 501-506.
[ Medline ]
4. Voltarelli JC, Stracieri ABPL. Aspectos imunológicos dos transplantes de células tronco
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study. Lancet 2000; 356: 701-707.
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8. White B, Moore WC, Wigley FM, et al. Cyclophosphamide is associated with pulmonary
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10. Fassas A, Anagnostopoulos A, Kazis A et al. Autologous stem cell transplantation in
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11. Zhao J, Fu Y, Peng X. Autologous hematopoietic stem cell transplantation in the
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transplantation, in press.
Recebido: 24/06/2002
Aceito: 22/07/2002
Division of Clinical Immunology and Bone Marrow Transplantation Unit, School of
Medicine of Ribeirão Preto, University of São Paulo, Brazil
Correspondence to: Júlio C. Voltarelli
Bone Marrow Transplantation Unit, Hospital das Clínicas, School of Medicine of Ribeirão
Preto, University of São Paulo. Ribeirão Preto. CEP: 14048-900. Brazil
E-mail: [email protected].
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