Hematopoietic stem cell transplantation for autoimmune diseases in Brazil: current status and future prospectives

O transplante de células precursoras hematopoéticas em doenças autoimunes no Brasil: estado atual e perspectivas

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 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).

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, 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 mg/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.

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

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: [e-mail].

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Publication Dates

• Publication in this collection
  14 Jan 2003
• Date of issue
  2002