Treatment of severe autoimmune diseases by immunoablative chemotherapy and autologous bone marrow transplantation

Abstract

The use of bone marrow transplantation for the treatment of refractory autoimmune diseases (AD) is a new concept that is starting to emerge based on many experimental data and some clinical observations obtained in the past 10 years after either allogeneic or, more recently, autologous bone marrow transplantation. Although experimental data demonstrate that allogeneic bone marrow transplantation is effective in treating refractory AD, the treatment-related mortality of such a procedure in humans even in the absence of underlying malignancy, is such that it should only be proposed for patients with refractory AD and an underlying hematological disorder requiring bone marrow transplantation. Autologous bone marrow transplantation, or peripheral hematopoietic stem cell transplantation (HSCT), is currently performed for the treatment of various malignancies including leukemia, lymphomas, or several solid tumors, and this procedure is associated with a low, short-term mortality (<3–5%). Therefore, on the basis of both experimental and clinical data, it has recently been considered an alternative approach to treating autoimmune diseases that are refractory to conventional treatment. Since 1996, an international consensus has emerged and helped to develop some national protocols with clear inclusion criteria, especially in cases of systemic sclerosis, vasculitis, lupus erythematosus, inflammatory myositis, and rheumatoid arthritis that are refractory to conventional treatment. The aim of these phase I–II pilot studies is to define the feasibility of this new procedure, which should still be considered as experimental. Data reporting is an integral part of the protocol. For the first 145 patients reported to the Basel registry, the mortality rate associated with the procedure is 8% (similar to that for non-Hodgkin's lymphoma), well below the estimated death probability at 6 months and 5 years for most of the diseases thus far treated.

Introduction

Several systemic autoimmune diseases (AD), when refractory to conventional treatments, are associated with a high mortality rate. This is due to the course of the disease and to the morbidity (essentially of infectious, vascular, or neoplastic origin) associated with long-term use of steroids and the immunosuppressive therapy given for refractory disease.

Although their exact mechanism remains unclear, these AD suggest anomalous T-lymphocyte function with polyclonal reactions involving B- and T-cell components, with regard both to the appearance of autoreactive T-lymphocytes and to anomalies in antigen presentation by the antigen-presenting cell (APC) or in the peripheral interaction between APC cells and T-lymphocytes 1, 2. The exact cell lineage(s) responsible for the appearance of these AD remain(s) unknown, but it has been demonstrated that all of the cells of the immune system derive from hematopoietic stem cells (HSC). Many experimental data [3]and several clinical observations 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15demonstrate the possibility of remission from an AD following allogeneic bone marrow transplantation. The opposite — i.e. the passive transfer of an AD from an allogeneic of bone marrow donor — has also been observed. Therefore, AD appear to be hematopoietic system-dependent [16]. Intensive myelosuppression and immunosuppression followed by HSC transplantation, could be an alternative therapy for severe AD 17, 18, 19. In this setting, HSC could be obtained from an allogeneic donor or from an autologous donor, from either the bone marrow or the peripheral blood.

In light of this knowledge, several European internists from the European League Against Rheumatism (EULAR) and hematologists from the European Group for Blood and Marrow Transplantation (EBMT) have considered the use of bone marrow transplantation for the treatment of some AD. This has led to a consensus report in order to better define the indications and the technical guidelines 17, 20. The importance of data reporting has been stressed since scientific analysis and evaluation of new techniques are an integral part of this new technique.

Even in the absence of an underlying hematological disorder or other malignancy, bone marrow allograft-related mortality has decreased within the last years. Yet, it continues to be reported [21]. Consequently, the use of allogeneic bone marrow transplantation must remain extremely limited for the treatment of AD, especially because of pre-existing organ damage related to AD. At present, it can only be proposed for homozygous twins or for AD in association with an underlying hematological disorder, which per se, justifies the risk associated with the allograft procedure. On the other hand, autologous bone marrow, or peripheral blood HSC, transplantation is currently indicated for leukemias, lymphomas, and several solid tumors 22, 23, 24, 25, with a risk-associated mortality of around 3 to 5% in 1999. On the basis of both experimental and clinical data, intensive immunosuppression followed by autologous HSC would appear to represent an ideal therapeutic alternative for patients with refractory AD whose mortality risk is clearly higher than that associated with this therapeutic procedure.

The aim of this review is to present (1) the experimental and clinical data that led to the development of this new therapeutic approach to AD, (2) the indications of the procedure in light of the European consensus and ongoing phase I–II studies, and (3) the preliminary results, as officially reported to the Basel registry since 1996.