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Sandoz-Keystone Symposium Abstracts |
Comprehensive Cancer Center, Rotterdam, The Netherlands
Centro Trapianti di Midollo Osseo, Divisione di Ematologia II, Ospedale San Martine, Genova, Italy
Rheumatologische Universitätklinik Basel, Felix Platter-Spital, Basel, Switzerland
Department of Neurology, University of Texas, Houston Health Science Center, Houston, Texas, USA
The New York Hospital-Cornell Medical Center, Department of Neurology and Neuroscience, New York, New York, USA
International Bone Marrow Transplant Registry and Autologous Blood Marrow Transplant Registry, North America, Statistical Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Key Words. Autoimmune diseases • Bone marrow transplantation • Rheumatoid arthritis • Multiple sclerosis • Myasthenia gravis
Dr. D.W. van Bekkum, Comprehensive Cancer Center Rotterdam, P.O. Box 289, 3000 AG, Rotterdam, The Netherlands.
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Introduction |
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 Top Introduction Immune Ablation Followed by...Experimental Basis for Treating...The Feasibility of Treating...Myasthenia GravisStem Cell Transplantation in...Toxicity of Blood and...DiscussionClinical Cases Reported at... |
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The clinical syndromes and identification of candidate patients for this treatment were successively discussed by clinical specialists in rheumatoid arthritis, myasthenia gravis and multiple sclerosis. In view of the lesser risks associated with autologous BM transplants, this option was preferred by the majority of the speakers. Recommendations were made for the design of the first exploratory trials, among them the establishment of a registry of such cases.
On this occasion, the core presentations were made for an audience of hematologists by clinicians specializing in each of the three major target diseases: rheumatoid arthritis, multiple sclerosis and myasthenia gravis. It was evident that clinical trials with this new approach are soon to begin, justifying the publication of a concise report of the proceedings of this discussion.
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Immune Ablation Followed by Stem Cell Infusion (Allogeneic, Autologous) for Severe Autoimmune Diseases |
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TopIntroductionImmune Ablation Followed by...Experimental Basis for Treating...The Feasibility of Treating...Myasthenia GravisStem Cell Transplantation in...Toxicity of Blood and...DiscussionClinical Cases Reported at... |
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Centro Trapianti di Midollo Osseo, Divisione di Ematologia II, Ospedale San Martine, Genova, Italy
General Introduction
More than 40 disorders are recognized at present as having an autoimmune etiopathology. Among them are a significant number of severe diseases that can only be partially controlled by conventional immunosuppressive (IS) treatments. This frustrating set of diseases can be found all over the spectrum of autoimmune disease (AID), but the most significant groups include autoimmune rheumatic diseases, especially in the treatment-resistant category, and neurological conditions, with multiple sclerosis in the foreground. These chronic AIDs make up the hard core of clinical autoimmunity. It must be pointed out that diseases may be confidently classified as "autoimmune" on the basis that defined reactions with self-antigens are the major pathogenic components in a multifactorial causation. Autoimmunity has been thought of as "not a result of particular forbidden clones, but rather as the persistent failure of an integrated fabric of components" [1] in which diverse factors such as infectious agents, molecular mimicry, loss of tolerance to (cryptic) self-peptides, failure to downregulate autoreactive T and B cells and the loss of apoptosis through involvement of the bcl-2 and FAS molecules all interact with autoimmune-inducing or predisposing genes. The concept of "autogenes" has been proposed recently [2] and experimental AIDs have been considered as "polyclonal stem cell diseases" [3]. However, the intricacies between intrinsic (genetic) and extrinsic causative factors and mechanisms are compounded by the diversities inherent in each AID, and even within a particular disease's subsets. This short recapitulation is intended to emphasize the complexities of a comparatively simple approach to therapy based on powerful immunosuppression followed by rescue with hematopoietic stem cells (HSC).
New Approaches to Therapy A few new approaches are currently being investigated. The first is based on T cell-directed immune interventions. Some clinical results are encouraging, but no cure has ever been claimed or even suggested. Although efforts to investigate the genetic background utilizing microsatellite-based genomic maps have been made in animal models of diabetes and in insulin-dependent diabetes mellitus (IDDM), and several predisposing loci on multiple chromosomes have been identified, gene therapy cannot be envisaged at this time.
On the other hand, powerful IS followed by allogeneic or perhaps even autologous HSC seems to offer interesting opportunities. Encouraging results have been reported incidentally in the clinic, and a rather solid basis has been provided in animal models.
Clinical Autoimmunity and Bone Marrow Transplantation (BMT)
Adoptive Autoimmunity
Three variants of autoimmune conditions have been observed after allo-BMT: genuine adoptive AID deriving from the documented transmission of BM cells from an affected or "carrier" donor, autoimmunity in the context of graft-versus-host disease (GVHD), and autoimmunity occurring in an apparently idiopathic way following either allo- or auto-BMT. Detailed references and additional information may be found in published reviews [4, 5]. A few outstanding examples will be mentioned here.
Autoimmune thrombocytopenia in the recipients may derive from the donor, develop in the context of chronic GVHD, or supervene in a primitive fashion, that is idiopathically, following both allo- and auto-BMT [4, 5].
Six reported cases of adoptive myasthenia gravis (MG) occurring after allo-BMT were collated in 1990 [6]. Once again, some relationship was found with chronic GVHD, and some special recipient haplotypes were found to be at risk for developing MG.
Another adoptive, post-transplant autoimmune condition is thyroiditis. In addition, concordant Graves' disease was described in an 18-year-old male and his 20-year-old sister, who had previously (8 years earlier) donated her marrow to her brother suffering from severe aplastic anemia (SAA).
IDDM is an autoimmune disease progressing from T cell sensitization to full-blown insulitis. A survey of IDDM cases related to allo-BMT has been recently performed by E.F. Lampeter (personal communication): 9 donors were affected by IDDM and, in two out of three patients with a follow-up of over two years, the disease developed in the recipients. In the other six cases with a shorter follow-up, because of patients' deaths within two years after transplantation, no diabetes had appeared.
Resolution of Pre-Existing AID following Allo-BMT
Although this is the most important area for the investigational therapy of AID, one can only rely on anecdotal experience. No patient has ever received an allo-BMT solely for an AID, however severe. The postulated autoimmune condition with the highest number of performed transplants (over 10 [4, 5]) is rheumatoid arthritis (RA). For almost all patients, the reason for transplantation was iatrogenic: gold-related SAA. One patient had a myelodysplastic syndrome. All patients had an initial complete clinical and immunological remission of their RA. However, three patients died of transplant-related toxicity and one died of hepatitis two years after transplant. Four are alive and well with no evidence of disease, but one has relapsed two years after allo-BMT even though her immune system is now entirely of donor origin [7]. This accurately investigated case with a 13-year follow-up illustrates that RA may recur and progress years after complete allogeneic marrow engraftment, perhaps by resensitization of a naive immune system to the same arthritogenic autoantigens. The long-term remission of another RA patient having received liver transplantation calls attention to the powerful IS rather than to the HSC switch [8].
A female patient with a clinical picture highly suggestive of systemic lupus erythematosus (SLE) (arthralgias, malar rash, pleuritis, alopecia, antinuclear antibodies of unreported pattern) developed SAA and was transplanted from her HLA-identical ABO-matched brother. She then developed pure red cell aplasia for which she was successfully treated with antithymocyte globulin. No relapse of the original condition has appeared up to 20 months after transplantation [9].
Finally, psoriatic arthritis and ulcerative colitis, concomitant with acute leukemias, have also resolved following allo-BMT [4, 5].
Autoimmune Diseases and Auto-BMT
The limited cases of this category can be further subdivided in patients having received unmanipulated or T cell-depleted (by virtue of positive selection of CD34+ cells) progenitors. Literature data are still scarce, although they are increasing rapidly.
In five patients with diverse AID who received unmanipulated autologous marrow after standard conditioning regimens, there were early recurrences. However, a long-term (three-year) clinical and immunological remission in a case of long-standing SLE having developed a lymphoblastic non-Hodgkin's lymphoma has also been reported.
Whether this and similar long-term remissions also obtained in multiple sclerosis are to be interpreted as the consequence of the eventual appearance of nonautoreactive (self-tolerant) lymphocytes, or more simply to the prolonged effect of powerful immunosuppression, cannot be stated at this time. However, in addition to already-published guidelines [10], it may be stated that patients affected with severe, treatment-resistant AID may be offered the option of powerful pulse IS (conventionally called "conditioning"), followed by autologous HSC rescue because of its greater safety versus allogeneic transplants. Techniques depleting autologous lymphocytes offer the chance of reducing the risk of relapse, thus making the procedure indicated also for the resolution of severe, life-threatening situations. The utilization of uniform conditioning regimens and the institution of an international registry will be essential.
References
1 Shoenfeld Y, Isenberg D. The Mosaic of Auto-immunity (The Factors Associated with Auto-immune Diseases). Amsterdam: Reed Elsevier, 1989.
2 Talal N. Oncogenes, autogenes, and rheumatic diseases. Arthritis Rheum 1994;37:1421–1422.[Medline]
3 Ikehara S. Intractable diseases and bone marrow transplantation. Pathol Int 1994;44:817–826.[Medline]
4 Marmont AM. Immune ablation followed by allogeneic or autologous bone marrow transplantation: a new treatment for severe autoimmune diseases? STEM CELLS 1994;12:125–135.[Medline]
5 Marmont AM. Stem cell transplantation for severe autoimmune disorders, with special reference to rheumatic diseases. J Rheumatol 1996 (in press).
6 Grau JM, Casademont J, Montforte R et al. Myasthenia gravis after allogeneic bone marrow transplantation: report of a new case and pathogenetic considerations. Bone Marrow Transplant 1990;5:435–437.[Medline]
7 McKendry R, Huebsch L, Leclaire B. Progression of rheumatoid arthritis (RA) following bone marrow transplantation (BMT). Arthritis Rheum 1996 (in press).
8 Lohse AW, Ono G, Hermann E et al. Remission of severe rheumatoid arthritis following liver transplantation. Br J Rheumatol 1993;32:827–828.[Medline]
9 Roychowdhury DF, Linker CA. Pure red cell aplasia complicating an ABO-compatible allogeneic bone marrow transplantation, treated successfully with antithymocyte globulin. Bone Marrow Transplant 1995;16:471–473.[Medline]
10 Marmont AM, Tyndall A, Gratwohl A et al. Haemopoietic precursor-cell transplants for autoimmune diseases. Lancet 1995;345:978.[Medline]
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Experimental Basis for Treating Autoimmune Diseases with Bone Marrow Transplantation |
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TopIntroductionImmune Ablation Followed by...Experimental Basis for Treating...The Feasibility of Treating...Myasthenia GravisStem Cell Transplantation in...Toxicity of Blood and...DiscussionClinical Cases Reported at... |
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Comprehensive Cancer Center Rotterdam, Rotterdam, The Netherlands
The manifold animal models of autoimmune diseases (AIDs) can be distinguished in hereditary and induced AID. The inherited types develop spontaneously with high frequency in specific inbred strains of rodents, but external factors such as diet and microflora may influence age of onset and incidence. The induced types require some type of immunization. Susceptibility or resistance to induction is strain-specific and therefore genetically determined. Many of the diseases in both categories can be transferred to healthy animals by grafts of bone marrow or lymphoid cells and, conversely, the diseases may be prevented by grafting cells from resistant donors into susceptible animals [1]. The logical next step was to investigate whether animals suffering from overt AID respond to transplantation of bone marrow from allogeneic-resistant donors, which, of course, requires myeloablative conditioning. One of the problems with allogeneic bone marrow transplantation (BMT) is the occurrence of graft-versus-host disease (GVHD) which, particularly in its chronic form, has many characteristics in common with AID. This complication was circumvented by Ikehara et al. [2] who were the first to cure fully developed AID in BXSB and in MLR/lpr mice with T cell-depleted allogeneic BM. In the MLR/lpr mice the disease recurred coincidentally with a reversal of the chimeric state. Recently, Karussis et al. [3] reported effective prevention of the development of disease manifestations in MLR/lpr mice by treatment with high-dose TBI or cyclophosphamide (CY) and rescue with syngeneic BM. CY proved more effective than TBI. Furthermore, T cell depletion of the BM graft produced better results than did unmanipulated marrow. In this experimental set-up, syngeneic marrow is derived from donors with an autoimmune-prone condition similar to the recipients, and is therefore equivalent with autologous marrow.
Similarly, induced adjuvant arthritis in rats [4] and induced encephalitis (EAE) in rats [5] responded with complete and lasting remission to transplantation of allogeneic BMT from resistant donors. Surprisingly, van Bekkum et al. found syngeneic (from the same susceptible inbred rat strain as the recipients) and autologous BM equally effective in inducing complete remissions as allogeneic BM in both the adjuvant arthritis [6] and the EAE (article submitted). Already in 1983, Prestonk et al. [7] reported complete recovery of rats with experimental autoimmune myasthenia gravis (EAMG) following combined conditioning with TBI and CY, and autologous BMT.
In adjuvant arthritis, spontaneous or induced (following reimmunization) relapses are rare events, even following autologous BMT, but in the EAE model the incidence of both types of relapses is higher with autologous marrow grafts. In the EAMG rats, spontaneous relapses did not occur, and reimmunization of the cured animals resulted in similar reactions as seen after primary induction.
In the EAE model, relapses were shown to be dependent on residual autoimmune T lymphocytes in the recipient as well as on the reintroduction of autoimmune T cells with the autograft [to be published and 8]. The latter observation provides a compelling indication for T cell depletion of the BM in the case of autologous grafts. High-dose myelo- and lymphoablative conditioning appears to be the best way to limit relapses originating from residual autoimmune cells.
The current but tentative explanation of the curative effect of autologous stem cells is recapitulation of the ontogenesis of the immune system, i.e., reconstitution of the immunological system originating from a limited number of pluripotent hemopoietic stem cells, resulting in tolerance.
As for the conditioning, this should be aimed at maximal reduction of reactive T cells and memory cells both in the inflamed sites and in the hematolymphatic tissues. This could be achieved most effectively with a lethal dose of TBI. Irradiation of the affected tissues (the central nervous system in the case of EAE, and the joints in the case of adjuvant arthritis) or of the lymphoid tissues with the affected tissues shielded resulted in incomplete responses of limited duration only [6, to be published and 8]. In adjuvant arthritis, fractionated TBI was found to be as effective as a single dose, provided the total dose was properly adjusted for time factor (to be published). Irradiation caused a transient exacerbation of the neurological symptoms of rats with EAE with some mortality. This did not occur when high-dose CY was employed for conditioning. In rats, the highest tolerated dose of CY was slightly less effective in adjuvant arthritis than TBI (to be published). In EAE rats, conditioning with a combination of CY and busulfan was somewhat less effective than with TBI, as judged by the incidence of relapses. In EAE mice, conditioning with CY and rescue with syngeneic BM resulted in complete remission of all animals with only 6% spontaneous relapses and 25% induced relapses; a comparison with TBI conditioning was not made [9].
In the EAMG model with autologous BM rescue, CY alone did not prevent significant anamnestic responses following reimmunization which was ascribed to surviving memory lymphocytes. Conditioning with CY and a sublethal dose of TBI did prevent the anamnestic responses [7].
There is an obvious paucity of information on the effectiveness of other lymphoablative agents for use in conditioning in animal models of AID. Agents like anti-lymphocytic serum (ALS) and cladribine could unfortunately not be tested in rats because of inadequate specificity or in humans because of differences in metabolism.
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2 Ikehara S, Yasumizu R, Inaba M et al. Long-term observations of autoimmune-prone mice treated for autoimmune disease by allogeneic bone marrow transplantation. Immunology 1989;86:3306–3310.
3 Karussis DM, Vourka-Karussis U, Lehmann D et al. Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation. Clin Exp Immunol 1995;100:111–117.[Medline]
4 van Bekkum DW, Bohre EPM, Houben PFJ et al. Regression of adjuvant-induced arthritis in rats following bone marrow transplantation. Proc Natl Acad Sci USA 1989;86:10090–10094.[Medline]
5 Van Gelder M, van Bekkum DW. Treatment of relapsing experimental autoimmune enceph-alomyelitis in rats with allogeneic bone marrow transplantation from a resistant strain. Bone Marrow Transplant 1995;15:583–590.[Medline]
6 Knaan-Shanzer S, Houben P, Kinwel-Bohre EPM et al. Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation. Bone Marrow Transplant 1991;8:333–338.[Medline]
7 Pestronk A, Drachman DB, Teoh R et al. Combined short-term immunotherapy for experimental autoimmune myasthenia gravis. Ann Neurol 1983;14:235–241.[Medline]
8 Van Gelder M, Kinwel-Bohre EPM, van Bekkum DW. Treatment of experimental allergic en-cephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transplant 1993;11:233–241.[Medline]
9 Karussis DM, Slavin S, Ben-Nun A et al. Chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE): treatment and induction of tolerance with high dose cyclophosphamide followed by syngeneic bone marrow transplantation. J Neuroimmunol 1992;39:201–210.[Medline]
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The Feasibility of Treating Severe Rheumatic Diseases with Bone Marrow Transplantation |
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TopIntroductionImmune Ablation Followed by...Experimental Basis for Treating...The Feasibility of Treating...Myasthenia GravisStem Cell Transplantation in...Toxicity of Blood and...DiscussionClinical Cases Reported at... |
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Rheumatologische Universitätklinik Basel, Felix Platter-Spital, Basel, Switzerland
Certain autoimmune rheumatic diseases fail to respond to conventional treatment and threaten life or vital organs. Some of these, for example, necrotizing vasculitis and cerebral lupus, may be treated successfully with immunosuppressive agents, particularly CY, and it seems logical to intensify this immune ablation under cover of hemopoietic stem cell rescue. In others, for example, systemic sclerosis with pulmonary fibrosis or pulmonary hypertension, there is less evidence of responses to conventional doses of CY, but as no other effective therapy exists, a trial of immune ablation and BMT is justified. A third and larger group of conditions consists of those in which the initial presentation is not dramatic, but with time a poor prognosis in terms of both morbidity and mortality develops with conventional therapy. Among those are rheumatoid arthritis in adults, juvenile systemic arthritis, psoriatic arthritis and SLE with nephritis, in which a clear benefit of CY has been recorded [1, 2].
The decision to treat with complete immunoablation and BMT requires a major shift in current management concepts. Recent data on long-term outcome in severe rheumatic disease [3], as well as early prognostic markers such as the shared rheumatoid epitope, have facilitated this shift. The so-called shared rheumatoid epitope is a sequence of amino acids in the third hypervariable region of the HLA-DR molecule and represents a sequence homology spanning codons 67-74. Combined with a positive rheumatoid factor, a relative risk of 13.5 of developing erosions within the next year was calculated in an English population [4]. Support for this new approach is not only provided by the results obtained in animal models of autoimmune diseases, but also by casuistic clinical data. A few patients with coincidental autoimmune rheumatic disease (rheumatoid arthritis, SLE and psoriatic arthritis) were treated with allogeneic BMT for aplastic anemia or malignant disease. Most patients experienced long-lasting remission of the autoimmune disease. Also, some early case reports have suggested a similar effect from autologous BMT, with indications that T cell purging reduces relapse rate.
Basic considerations for guiding the initial attempts to treat selected patients with BMT may be summarized as follows:
References
1 Euler HH, Schroeder JO, Harten P et al. Treatment-free remission in severe systemic lupus erythematosus following synchronization of plasmapheresis with subsequent pulse cyclo-phosphamide. Arthritis Rheum 1994;37:1784–1794.[Medline]
2 Shaikov AV, Maximov AA, Speransky AI et al. Repetitive use of pulse therapy with methylprednisolone and cyclophosphamide in addition to oral methotrexate in children with systemic juvenile rheumatoid arthritis — preliminary results of a long-term study. J Rheumatol 1992;19:612–616.[Medline]
3 Pincus T. The case for early intervention in rheumatoid arthritis. J Autoimmun 1992;5:209–226.[Medline]
4 Emery MC, Salmon M. Early rheumatoid arthritis: time to aim for remission? Ann Rheum Dis 1995;54:944–947.[Medline]
5 Hochberg MC. Systemic lupus erythematoaia. Rheum Dis Clin North Am 1990;16:617–639.[Medline]
6 Steen VD, Medsger TA Jr, Rodnan GP et al. D-penicillamine therapy in progressive systemic sclerosis (scleroderma). Ann Intern Med 1984;97:652–659.
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Myasthenia Gravis |
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Department of Neurology, University of Texas, Houston Health Science Center, Houston, Texas, USA
Myasthenia gravis (MG) is an AID caused by autoantibodies against nicotin-acetylcholine receptors (ACR). As a result of interaction between the autoantibodies, the ACR and complement, the receptors are blocked and postsynaptic surface membranes are damaged. This process causes the clinical picture of fluctuating skeletal muscle weakness which may affect the ocular and oropharyngeal muscles, the limbs and the respiratory muscles. The autoantibody response is T cell-dependent; there is a genetic predisposition to the disease.
The prevalence of MG is 50-125 per million; in the USA the number of patients is estimated at 25,000. It affects all ages with peaks in the second and third decade among women and in the sixth to seventh decade among men. Eighty-five percent of patients have generalized disease and in 15% it is limited to the ocular muscles. In 15% a thymoma is found, and 60% have thymus hyperplasia. Associated AIDs such as diabetes mellitus, thyroiditis, Graves' disease, systemic lupus erythematosus and rheumatoid arthritis are common.
Most patients under 60 with generalized disease are treated with thymectomy, because this may result in long-lasting remission. However, complete remission is rare and there is often a long delay until improvement sets in. Drug treatment is with cholinesterase inhibitors, for example, mestinon, and 60%-70% receive immunosuppressive (IS) drugs such as corticosteroids, azathioprine and cyclosporine. Acute exacerbations necessitating ventilatory support and hospitalization may occur. These so-called crises are treated with plasmapheresis or i.v. immune globulins.
Only about 7% of all patients go into spontaneous remission (no treatment); 18% respond to short-term IS treatment; the remainder require long-term immunosuppression. The majority of the latter group benefit with improvement, but about 5% continue to suffer from recurrent crises and persistent muscle weakness.
Overall mortality is 4%-7%, some of which is likely due to treatment toxicity. The most prevalent side effects are due to corticosteroids and include: cataracts, osteoporosis, weight gain, hypertension, gastrointestinal ulcers, diabetes, infections, aseptic hip necrosis and cushingoid face.
Response to treatment can be reliably and quantitatively determined by measuring muscle strength, vital capacity, repetitive nerve stimulation, single-fiber EMG and reduction of antibody titer against ACR.
Accordingly, it appears that about 5% of MG patients, namely, those not responding to long-term IS treatment, are potential candidates for BMT. In contrast with the effects of arthritis and multiple sclerosis, the lesions in MG are reversible because the neuromuscular junctions usually regenerate once the immune reaction has been abrogated. Therefore, the timing of BMT does not seem to be as crucial as in the other diseases. However, a low toxicity BMT protocol is required, as MG is not an acutely life-threatening disease. That criterion appears to be fulfilled by the use of autologous bone marrow. Allogeneic BMT carries a higher risk; moreover, a significant number of patients have developed MG after allo-BMT, probably related to clinical graft-versus-host disease, as was mentioned by Marmont. In MG a specific issue has to be considered, namely, that most if not all patients have been previously subjected to thymectomy. How far would the absence of the thymus in an adult impair the immune reconstitution after BMT? An additional question to be posed is whether T cell depletion of the graft is justified in these patients.
References
1 Drachman DB. Myasthenia gravis. N Engl J Med 1994;25:1797–1810.
2 Lisak RP, ed. Handbook of Myasthenia Gravis and Myasthenic Syndromes. New Jersey: Marcel Dekker, 1994.
3 de Baets MH, Oosterhuis HJGH, eds. Myasthenia Gravis. Boca Raton, FL: CRC Press, 1993.
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Stem Cell Transplantation in the Treatment of Multiple Sclerosis |
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TopIntroductionImmune Ablation Followed by...Experimental Basis for Treating...The Feasibility of Treating...Myasthenia GravisStem Cell Transplantation in...Toxicity of Blood and...DiscussionClinical Cases Reported at... |
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The New York Hospital-Cornell Medical Center, Department of Neurology and Neuroscience, New York, New York, USA
Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system of presumed autoimmune etiology [1–3]. Infiltrates of T cells, B cells and macrophages in brain pathology indicate an immunologically mediated disease process which can cause severe neurologic dysfunction. As in other autoimmune conditions, there are predisposing immunogenetic HLA determinants, with possibly some initiating infection or environmental components. MS occurs in a young patient population with onset typically between the ages of 20 and 40, affecting women more commonly than men. The clinical manifestations of MS are diverse, depending upon the extent of involvement of the central nervous system. The disease course at onset is often relapsing-remitting, with acute attacks of neurologic dysfunction followed by variable improvement. In more advanced disease, there can be a chronic-progressive course with gradual neurologic deterioration.
MS has a broad spectrum of disease severity, ranging from "benign" to "malignant" forms. In benign MS there are infrequent exacerbations over decades, with mild sensory symptomatology and minimal disease on brain MRI. With malignant forms of the disease, however, there can be rapid clinical progression over one to five years with reduced survival. The neurologic disability in severe MS can include quadraparesis, blindness, dementia, loss of bowel and bladder control, impaired swallowing and respiratory function and conditions of chronic pain. Brain MRI scans document extensive lesions throughout the central nervous system in such severe forms.
The conventional treatment of MS has relied on immunosuppressive agents, including corticosteroids, azathioprine, CY, cyclosporine and methotrexate, with only limited success in controlling disease [1–3]. Total lymphoid irradiation at lymphoablative doses has shown temporary benefits for chronic-progressive MS [3]. Newer potent lympholytic drugs such as cladribine may also have modest benefits in slowing the rate of progression [4]. Other immunomodulatory therapies such as interferon-ß have been shown to reduce attack frequency and brain lesions in milder relapsing-remitting forms of disease. However, no standard therapy is curative or uniformly successful in controlling severe forms of disease. Given the recent advances in hematopoietic stem cell transplantation for leukemia and lymphoid malignancies with reconstitution of the immune elements [5], a compelling rationale exists for examining the potential benefits of stem cell transplantation in the treatment of MS and other autoimmune conditions of the central nervous system.
Despite the refinements in stem cell transplantation therapy in recent years, the potential risks of treatment dictate its use for more severe, disabling forms of MS. Given the highly variable clinical course in MS, however, the selection of patients for stem cell transplantation is not straightforward. With a broad spectrum of clinical disability in MS, the prognosis at disease onset can be uncertain. Certain clinical features help define more malignant forms of disease, including frequent relapses with rapidly progressive neurologic disability and minimal response to conventional therapies. Brain MRI studies should typically demonstrate a correspondingly heavy burden of demyelinating disease. Patient selection criteria for the stem cell transplantation protocol must be designed to provide an early assessment of such prognostic indicators for a malignant course of MS. The rapid implementation of a treatment protocol in such carefully selected patients before permanent, advanced neurologic disability occurs is important for an optimal outcome.
In addition to defining clinical indications for stem cell transplantation in the treatment of severe forms of MS, a protocol must establish objective outcome measures of response to therapy. Current treatment trials in MS employ standardized disability scores to assess progression of disease as a primary endpoint of therapy. Quantitative brain MRI analysis is a sensitive indicator of new or enlarging lesions on serial scans correlating with clinical disability. The use of gadolinium contrast-enhancement of focal brain lesions provides another measure of disease activity. Prolonged delays in the responses of motor- and sensory-central-evoked potentials can precisely measure the degree of demyelination throughout the nervous system. As yet, no hematologic laboratory marker of disease activity, such as autoreactive T cells, exists.
It is hoped that investigators can establish the degree of clinical response to stem cell transplantation using these objective parameters of disease activity, whether they be slowing the progression of MS, stabilization of the disease or possible improvement in neurologic disability. Many unknown issues remain to be explored in the use of stem cell transplantation as a "curative" therapy for MS or other severe autoimmune disease. If improvement of disease occurs, what is the degree and duration of clinical remission that may be expected with stem cell reconstitution of the immune system? Clearly, long-term follow-up of MS patients will be required to answer questions of safety and efficacy of stem cell transplantation. Since the primary etiology and pathogenesis of MS remain obscure, the use of advanced hematopoietic stem cell reconstitution following immune ablation may improve our limited understanding of the immunogenetic and environmental factors underlying this difficult disease.
Animal models of MS having experimental autoimmune encephalomyelitis have been successfully treated with lethal doses of TBI and conditioning regimens of cytoreductive drugs followed by autologous, syngeneic or allogeneic BMT [6, 7]. However, there is very limited experience with stem cell transplantation in the treatment of MS patients. Experiments treating rats with relapsing autoimmune encephalomyelitis by allogeneic bone marrow transplants from a resistant strain result in reinduction of disease in autoimmune encephalomyelitis-susceptible strains. Such a theoretical benefit of allogeneic transplantation in humans for preventing the recurrence of MS is unknown. A limited number of cases of persons with MS who received allogeneic BMT primarily for leukemia or other concomitant malignancies showed significant systemic complications of GVHD. The unknown advantages at this time of allogeneic transplantation for MS may not outweigh the established increased complication rate of GVHD. Further, since an HLA-matched sibling would also carry an increased risk for MS, given the same immunogenetic pattern of autoimmune disease susceptibility, allogeneic transplantation might not confer a great advantage for MS disease remission.
Autologous peripheral blood stem cell transplantation specifically for the treatment of MS has been performed in two MS patients with more advanced disability and progressive disease of several years' duration by Fassas et al. [8]. Peripheral blood stem cells were mobilized by CY and G-CSF, followed by high-dose chemotherapy (BEAM regimen of BCNU, VP-16, AraC and Melphalan), and antilymphocyte immunoglobulin was administered on days +1 and +2. These MS patients have had an uncomplicated course several months post-transplantation with minor clinical improvement. The use of autologous transplantation protocols will most likely require standard regimens of T cell depletion of stem cells to eliminate residual autoreactive lymphocytes.
Total lymphoid irradiation has been applied in treatment of MS with temporary benefits in slowing progression of disease when used at lymphoablative doses (up to 50% delivered to the spinal column but excluding the brain) [3]. There is anecdotal evidence, however, that whole-brain irradiation may be deleterious to the course of MS, in some cases negatively affecting the inflammatory demyelinating process [9]. At this time it is unknown whether TBI is a necessary or desirable part of a conditioning regimen for stem cell transplantation in MS. The additional application of irradiation to high-dose immunosuppressive chemotherapy in protocols for MS will require cautious empirical testing.
If the benefits of stem cell transplantation for MS are supported by initial investigational studies, then larger trials using randomized controlled treatment protocols are in order. At present, the relatively contained immediate risk of stem cell transplantation may be outweighed by the potential long-term benefit of immune reconstitution in treating malignant forms of MS, particularly given the lack of alternative therapies. With over 250,000 estimated patients in the United States alone, 10% of the most severe MS cases represent up to 25,000 candidates whose outcome might be favorably altered by an advanced stem cell transplantation protocol. The role of transplantation in the treatment of other severe forms of autoimmune diseases of the nervous system (e.g., chronic inflammatory demyelinating polyradiculopathy, primary arteritis of the brain and paraneoplastic syndromes) which are refractory to conventional management remains to be tested.
References
1 Hafler DA, Weiner HL. Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev 1995;144:75–107.[Medline]
2 Antel JP. Multiple sclerosis. Neurol Clin 1995;13:1–227.[Medline]
3 Cook SD, ed. Handbook of Multiple Sclerosis. New York: Marcel Dekker, 1990.
4 Beutler E, Sipe JC, Romine JS et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci USA 1996;93:1716–1720.[Abstract]
5 Tyndall A, Gratwohl A. Haemopoietic stem and progenitor cells in the treatment of severe autoimmune disease. Ann Rheum Dis 1996;55:149–151.[Medline]
6 Van Gelder M, van Bekkum DW. Treatment of relapsing experimental autoimmune enceph-alomyelitis in rats with allogenic bone marrow transplantation from a resistant strain. Bone Marrow Transplant 1995;15:583–590.[Medline]
7 Burt RK, Burns W, Hess A. Bone marrow transplantation for multiple sclerosis. Bone Marrow Transplant 1995;16:1–6.[Medline]
8 Fassas A, Anagnostopoulos A, Kazis A et al. Peripheral blood progenitor transplantation for treatment of multiple sclerosis. Bone Marrow Transplant 1996;17(suppl 1):S6.
Note added: At the EBMT meeting in Vienna, March 4 1996, Fassas reported continued improvement of the two patients described in his abstract, as well as treatment of five more MS patients with the same regimen of bone marrow transplantation. During the discussion following his presentation it was suggested that the post-transplant administration of antilymphocyte immunoglobulin may well have resulted in in vivo T cell depletion of the graft.
9 Peterson K, Rosenblum MK, Powers MD et al. Effect of brain irradiation on demyelinating lesions. Neurology 1993;43:2105–2112.[Abstract]
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Toxicity of Blood and Marrow Transplantation: Data from the IBMTR and ABMTR |
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International Bone Marrow Transplant Registry and Autologous Blood Marrow Transplant Registry, North America, Statistical Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Toxicity of Autotransplants
High-dose therapy with hematological rescue using cells from the patient's own blood or marrow (autotransplant) has fewer immunological complications than transplants using cells from an allogeneic donor. In allogeneic transplants GVHD and immune suppression accompanying its treatment are major causes of morbidity and mortality. Autotransplants may suffer effects from harvesting marrow and/or blood cells, maintenance of long-term venous access and chemotherapy and/or radiation toxicities to hematopoietic and nonhematopoietic organs. Hematopoietic toxicities may be effectively managed as long as sufficient doses of stored progenitor cells are administered to the patient. Nonhematopoietic toxicities may involve the heart, lungs, liver, kidneys, bladder, gonads and nervous system. These organs may have increased susceptibility to injury due to the underlying disease or its prior therapy. Secondary cancers are also reported after autotransplants. The causal contributions to second cancers of underlying disease, prior therapy and transplant have yet to be determined.
Early Mortality Following Autotransplants and Allogeneic Transplants
The Autologous Blood and Marrow Transplant Registry-North America has data on over 18,000 autotransplants performed since 1989 in North and South America. The International Bone Marrow Transplant Registry has data on over 33,000 allogeneic and syngeneic transplants performed worldwide since 1968. For patients with malignancy, 100-day mortality has decreased significantly for both autotransplants and allogeneic transplants from 1990 to 1995. In autotransplants, 100-day mortality is <5% for patients with favorable prognostic features. It may be as high as 20% for those with unfavorable features such as transplant in relapse or advanced disease stage, older age, lower Karnofsky score pretransplant or extensive prior therapy. In allogeneic transplants 100-day mortality rates range from 15% to 25%. Prognostic factors are similar to those of autotransplants but additionally affected by the type of donor (family or unrelated) and degree of HLA match.
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Discussion |
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Patient Selection
Each of the specialists speaking on arthritis, multiple sclerosis and myasthenia gravis, respectively, had already clearly outlined what patient criteria might be applied. There was agreement that within each disease a small subgroup of patients can be identified as suitable candidates. In MS and arthritis, it is essential to treat before the irreversible lesions—demyelination and osseous deformities respectively—are too far advanced. In MG, this is less crucial because the functional sequelae are essentially reversible.
Conditioning
Basically, the choices are TBI, one or more chemotherapeutic agents and specific antilymphocytic agents such as antilymphocyte globulin or various combinations. van Bekkum stressed once more that the rationale of the treatment is to abrogate the autoimmune reaction and to allow recapitulation of ontogeny to establish tolerance. The purpose of conditioning is the eradication of autoreactive lymphocytes, including memory cells. Accordingly, conditioning should be as radical as possible. In the animal models, the frequency of spontaneous and induced relapses is positively related to the number of residual autoreactive lymphocytes surviving the conditioning. However, heavy conditioning entails greater toxicity. Most speakers felt that TBI should be avoided because it carries the risk of increased tumor incidence.
CY is favored by many to begin with in clinical trials. High-dose CY has a long-standing reputation in allogeneic BMT and was effective in curing another AID, i.e., aplastic anemia. Treatment with medium-dose pulsed CY has been effective in some arthritic patients, causing long-lasting remissions. Unfortunately, it is not known if CY is capable of inactivating memory T cells. Antilymphocyte globulin and cladribine were considered suitable for combining with CY to increase the lymphocytolytic impact of the conditioning. For technical reasons, these two agents cannot be used in investigations with animal models of AID.
Auto- or Allografts
Autologous BM has the advantages of not requiring a donor and of less transplant- related toxicity: no-take failures and no GVHD. On the other hand, many felt that in the event that an HLA-identical donor is available, allogeneic bone marrow is to be preferred because there is no reinfusion of diseased cells as in autologous BMT. Furthermore, with proper prophylaxis, GVHD has become much less of a threat, and some pointed out that in the very sensitive EAE model, allogeneic BM proved to be superior in prevention of both spontaneous and induced relapses. So we shall probably see both options explored in future clinical trials.
T Cell Depletion
The reinfusion of autologous BM without prior T cell depletion is sure to reimplant considerable numbers of autoreactive T lymphocytes. Data from animal models, in particular EAE, also argue strongly against the use of nondepleted autologous grafts. However, there is widespread concern that T cell depletion will delay immunological recovery and thereby increase the risk of infections during the post-transplant period. Such concern is not based on experimental evidence. Currently, available methods which allow large-scale positive selection of hemopoietic precursors (CD34+ cells) also reduce T cells by two to three logs. This technology has been used for autologous peripheral blood precursor cells to rescue cancer patients after high-dose chemotherapy. According to R. Mertelsmann (Freiburg, Germany), immune recovery was identical to that in unmodified peripheral blood precursor cells, except in patients after BU/CY where T cell reconstitution took one week longer. Since preliminary results with nondepleted autologous BM in a few patients with systemic lupus erythematosus indicated early relapses, there was a general feeling that T cell depletion should be attempted and that, whatever method was used, one should determine the number of T cells reinfused.
Is Previous Thymectomy a Contraindication?
BMT in lethally irradiated mice that had been thymectomized at birth resulted in a much delayed and incomplete recovery of T lymphocyte numbers. Removal of the thymus during adulthood has less dramatic effects. The current opinion among immunologists is that in the adult organism, differentiation and maturation of T cells is much less thymus-dependent than during the perinatal period. A. Gratewohl (Basel, Switzerland) reminded us that patients suffering from pure red cell aplasia were usually thymectomized and that they did not experience delayed immune recovery following allogeneic BMT. Furthermore, it was brought forward that thymectomy in adults is probably incomplete; the remnants might contain sufficient epithelial cells to support T cell differentiation. In conclusion, no compelling reasons were brought forward to exclude thymectomized MG patients from BMT. In those cases, a more detailed monitoring of the immune parameters after transplantation is to be recommended.
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Clinical Cases Reported at the Session |
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Dr. Kang Howson-Jan (Department of Hematology-Oncology, London Health Science Centre, London, Canada) has transplanted three MS patients. One patient was transplanted with autologous BM following high-dose VP-16 and melphalan for non-Hodgkin's lymphoma. She was diagnosed with lymphoma before the work-up of her MS was completed. She had unilateral optic neuritis and MRI criteria for MS. She has not developed any further neurological symptoms since she started treatment for non-Hodgkin's lymphoma. Follow-up is now three months post-BMT.
The second patient had MS diagnosed three years prior to her diagnosis of acute lymphocytic leukemia (ALL). She relapsed six months after an autologous BMT (non-T cell-depleted) after conditioning with chemotherapy including vincristine, solumedrol, L-asparaginase and CY and 600 cGy of TBI. She died soon after an attempt at reinduction. Just prior to her relapse, she reported an increase in the number of falls at home. This and autopsy data of the brain seemed to suggest progression of her MS.
The third patient had stable MS with a sensory neuropathy involving his arms and legs two years prior to developing acute myelogenous leukemia (AML). He received an allogeneic BMT following induction and consolidation. Conditioning was with BU/CY and GVHD prophylaxis with methotrexate and cyclosporine. He has been without immunosupressives for seven months and is now in complete remission for 14 months post-transplant. There has been no change in his MS.
Dr. James Russell (Tom Baker Cancer Centre, Calgary, Canada) reported two patients with MS. The first was a 44-year-old man with a five-year history of chronic progressive MS who received an allogeneic graft of peripheral blood precursor cells for myelodysplastic syndrome in January 1994. Conditioning was with BU/CY and GVHD prophylaxis with methotrexate and cyclosporine. At four months post-transplant, he had an exacerbation of his MS. Following a protracted hospital course with recurrent infections, he died, eight months post-transplant.
The second patient was a 38-year-old female with an eight-year history of relapsing remitting MS, progressing to a wheelchair-bound condition a year after diagnosis. She was diagnosed with AML in March 1995, and received an allogeneic T cell-depleted peripheral blood cell transplant after conditioning with CY, antithymocyte globulin, thiotepa and 500 cGy single fraction TBI, followed by GVHD prophylaxis with cyclosporine and corticosteroid treatment of evolving acute GVHD. To date, her MS remains reasonably stable.
accepted for publication April 8, 1996.
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