Haematological stem cell transplantation in the treatment of severe autoimmune diseases: first experiences from an international project

Series Editor: P. Woo

A. Tyndall

Department of Rheumatology, University Hospital Felix Platter Spital, Burgfelderstrasse 101, Basel 4012, Switzerland

The use of profound immunosuppression in the treatment of severe autoimmune disease (AD) is routine. Experience ranges from the use of established regimens of cyclophosphamide and prednisone in Wegener's granulomatosis (WG) and renal systemic lupus erythematosus (SLE), to anecdotal or experimental modalities in rarer disorders.

A common theme running through these experiences is the failure of `conventional' immunosuppression to control a life- or vital organ-threatening immunologically mediated event, and a lack of proven alternatives. Another recurring problem is the limitation of bone marrow toxicity related to the intensity of immunosuppression.

Recent developments in haemopoietic stem cell transplantation (HSCT) have brought a level of safety which allows it to be considered as a therapeutic option for AD treatment [1]. Autologous HSCT following haematoimmunoablation is more a support or rescue event, rather than bone marrow transplantation (BMT) in the classical sense. This concept is supported by anecdotal experience in patients undergoing BMT for conventional diseases with coincidental AD [2], animal models [3] and early pilot study experience [4].

Bone marrow transplantation

In the past 10 yr, autologous HSCT has surpassed allogeneic BMT in numbers, as has peripheral blood stem cell vs bone marrow acquired (harvested) source. HSCs may be mobilized from the marrow (primed) using growth factors such as granulocyte colony-stimulating factor (G-CSF) with or without a bolus dose of a cytotoxic drug such as cyclophosphamide. Such a peripheral harvest may be performed as an out-patient procedure, and the HSCs obtained then frozen and stored.

Following this harvesting, the patient is brought back, usually about 1 month later, for an ablative therapy (conditioning) consisting of chemotherapy plus or minus combinations of total body irradiation (TBI) and antibodies such as antithymocyte (ATG), antilymphocyte (ALG) or other serotherapy, e.g. CAMPATH 1.

The stored HSCs are then reinfused, with or without ex vivo manipulation, which is known as graft product engineering or purging. In the past, such graft manipulation was employed to reduce the load of unwanted cells, such as malignant cells in cancer therapy or T cells to reduce graft-vs-host disease in allogeneic BMT. In autologous HSCT, so far there has been no need to purge heavily T or other immune-competent cells. Indeed, immune cells have been desired to enable rapid reconstitution of the immune function post-transplant [5].

Coincident autoimmune disease and BMT

There have been a number of case reports of patients receiving BMT for conventional reasons, such as aplastic anaemia or malignancy, in whom a coincident AD was improved or cured. Original reports were allogeneic and, especially in rheumatoid arthritis (RA) with aplastic anaemia, long-term disease-free remissions have been reported [6]. More recently, autologous HSCT has been added to the list, and the ADs have included RA, SLE, myasthenia gravis, multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis with and without arthritis, insulin-dependent diabetes mellitus and others [7, 8].

These reports are important, but have the limitation of biased reporting towards positive outcome, and sometimes limited data on AD severity and extent of organ involvement. Also, the conditioning regime given for a malignancy is often more severe than that being proposed for AD alone. However, some detailed reports demonstrate that AD may recur after apparently successful allografting for RA, and that the donor cells are responsible [9].

Taken together, these cases demonstrate that BMT may significantly alter the natural history of AD in selected cases.

Bone marrow transplantation for autoimmune disease alone

The International Autoimmune Stem Cell Project, originally started under the auspices of the European Group for Blood and Marrow Transplantation (EBMT) and EULAR, has since expanded to include data from other centres in the USA and Australia, and other autoimmune diseases such as multiple sclerosis and autoimmune enteropathy.

There are currently 110 patients entered into this database, 107 having received an autologous HSCT. An interim analysis of the first 99 autologous transplants shows the following results.

Disease categories, etc.

Neurological

Rheumatic diseases

Haematological

Treatment

Stem cell source

Stem cell mobilization

Conditioning regimens

Purging

Most groups followed set protocols generated from several centres, disseminated through the stem cell project centre in Basel or other major US centres and consistent with guidelines established through a consensus meeting held in September 1996 [10].

Toxicity

Patients mobilized but

Patients transplanted

Type of death (infection, haemorrhage) and incidence of procedure-related death similar to a control group of lymphoma patients treated during the same period in the same centres (6%). Total procedure-related death: SSc, 3; multiple sclerosis, 3; RA, 1; `a total of 7/110 =6.36%'.

Outcome
In 56 patients, a partial or complete response was reported, measured according to disease type, e.g. multiple sclerosis, improvement of at least one point in the EDSS functional assessment or SSc improved skin score or pulmonary infiltrate, lung diffusion capacity, etc. `No response' reported in 24 and not evaluable in 17.

From the current data, there seems to be no indication that any particular ablative conditioning or purging regimen is superior to another with respect to remission induction or relapse. Heavily T-cell-purged adults had a tendency toward prolonged CD4 T-cell penia, with increased infection rate.

Summary

The benefit:risk ratio of HSCT in autoimmune disease appears to justify the initiation of prospective controlled comparative studies. The comparator arm is open, one possibility being mobilized (Cy 2 or 4 g/m2 +G-CSF), but not transplanted. Inclusion and exclusion criteria for different disease categories need to be standardized, as do outcome measurements.

In Europe, the EBMT has established a new working party for autoimmune disease with representatives from all involved groups, including the USA. A similar parallel group is being established in North America. The aim will be consensus and standardization of disease-specific aspects. Standardization of immune reconstitution parameters could prove critical in the understanding of autoimmune mechanisms, with early guidelines being developed and available to interested groups.

Data collection is critical, with advanced discussions on common registration forms between the EBMT and the American Bone Marrow Transplantation Registry (ABMTR) already taking place. Common detailed disease-specific clinical data forms are now a top priority, so that data from the two major databases may be compared.

All patients fulfilling entry criteria should be registered and followed long term, including those not able to be treated for non-medical reasons, such as insurance. This will provide a prospective `conventional treatment' control group.

Regular and flexible liaison between the data managers of both groups will be encouraged, as with regulatory authorities such as the Food and Drug Administration. The following such meeting was in Basel, 8–10 October 1998.

References

  1.  Snowden JA, Brooks PM, Biggs JC. Haemopoietic stem cell transplantation for autoimmune diseases. Br J Haematol 1997;99:9–22.[ISI][Medline]
  2.  Messner RP. The potential of bone marrow stem cell transplantation in the treatment of autoimmune diseases. J Rheumatol 1997;24:819–21.[ISI][Medline]
  3.  Van Bekkum DW. BMT in experimental autoimmune diseases. Bone Marrow Transplant 1993;11:183–7.[ISI][Medline]
  4.  Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakallari I, Kimiskidis V et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis—first results from a pilot study. Bone Marrow Transplant 1997;20:631–6.[ISI][Medline]
  5.  Roux E, Helg C, Dumont-Girard F, Chapuis B, Jeannet M, Roosnek E. Analysis of T cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T cell depleted and unmanipulated grafts. Blood 1996;87:39–84.
  6.  Lowenthal RM, Cohen ML, Atkinson K, Biggs JC. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol 1993;20:137.[ISI][Medline]
  7.  Nelson JL, Torrez R, Louie FM, Choe OS, Storb R, Sullivan KM. Pre-existing autoimmune disease in patients with long term survival after allogeneic bone marrow transplantation. J Rheumatol 1997;24(suppl. 48):23.[ISI]
  8.  Meloni G, Capria S, Vignetti M, Mandelli F, Modena V. Blast crisis of chronic myelogenous leukemia in long-lasting systemic lupus erythematosus: regression of both diseases after autologous bone marrow transplantation. Blood 1997;89:46–59.
  9.  McKendry RJR, Huebsch L, Lelair B. Progression of rheumatoid arthritis following bone marrow transplantation. A case report with a 13-year follow up. Arthritis Rheum 1996;39:1246–53.[ISI][Medline]
  10. Tyndall A, Gratwohl A. Blood and marrow stem cell transplants in auto-immune 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;19:643–5.[ISI][Medline]
Accepted 15 March 1999