Feasibility of Allogeneic Hematopoietic Stem Cell Transplantation for Autoimmune Disease: Position Statement from a National Institute of Allergy and Infectious Diseases and National Cancer Institute–Sponsored International Workshop, Bethesda, MD, March 12 and 13, 2005

Article Outline

• Introduction
• Rationale for allogeneic hematopoietic transplantation as therapy for autoimmune disease
• Disease candidates and patient populations
• Transplantation regimens
• Stem cell source
• Donor source
• Graft manipulation
• Role of chimerism
• Donor lymphocyte infusions
• Issues in clinical trial designs
• Other open research questions
• Conclusion/Next steps
• Acknowledgments
• Appendix 1. Workshop participants
  • Cochairs
  • Speakers and Discussants
    • Hematopoietic cell transplantation
    • Neurology, neuropathology, and neurologic imaging
    • Rheumatology and allergy-immunology
• References
• Copyright

Key words:  Allogeneic hematopoietic cell transplantation , Autoimmune disease , Clinical trial

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Introduction 

The primary objective of this 1.5-day workshop was to critically explore and identify the rationale for clinical trials of allogeneic hematopoietic cell transplantation (HCT) in autoimmune diseases, with particular emphasis on multiple sclerosis (MS) and systemic sclerosis. Meeting participants were HCT physicians and autoimmune disease experts from North America and Europe. The focus of these discussions was to define diseases and patient populations that may benefit from allogeneic HCT, by rethinking disease pathophysiology and natural history in light of today’s allogeneic HCT technology. We evaluated transplantation protocols, each consisting of a transplantation regimen and associated graft-versus-host disease (GVHD)–prevention regimen, with regard to the risk-benefit ratio for patients with autoimmune diseases. Patients appropriate for allogeneic HCT approaches will be infrequent, and such individuals should be enrolled in approved research protocols conducted by multidisciplinary teams at highly experienced centers. In this report, we provide general recommendations for how such clinical trials should be pursued in the immediate future.

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Rationale for allogeneic hematopoietic transplantation as therapy for autoimmune disease 

Allogeneic HCT is widely accepted as curative therapy for several malignant and nonmalignant diseases [1, 2]. It eradicates the host lymphohematopoietic system and provides a new and potentially healthy donor-derived immune system, which may also convey a lesser genetic risk for recurrent autoimmune disease. The allogeneic graft also exerts an immune-mediated graft-versus-host effect that is important for successful engraftment and may be responsible for the poorly understood clinical phenomenon called the graft-versus-autoimmunity effect. In some cases, allogeneic HCT is associated with the establishment of mixed hematopoietic chimerism, which may modulate the host immune system sufficiently to induce remission from the autoimmune disease. Animal models of autoimmune disease [3], extensive experience in patients with aplastic anemia [4, 5, 6], and a series of published clinical case reports in patients with systemic autoimmune disease [7, 8, 9, 10, 11, 12] provide evidence that allogeneic HCT may cure patients with autoimmune disease. Because currently available standard therapies for patient populations with severe autoimmune diseases are only partly effective and are not curative, patients are typically exposed to maintenance or reinduction therapies that create cumulative toxicities, costs, and negative effects on quality of life. Studies of high-dose immunosuppressive therapy with autologous HCT have been promising, but safety and response durability are still being investigated, and not all patients will tolerate the high-dose regimens.

The potential for 1-time delivery of a curative therapeutic strategy is appealing. The introduction of lower-intensity nonmyeloablative conditioning regimens and better prevention and treatment of both GVHD and infections have improved the safety profile of allogeneic HCT. These advances have made investigative studies involving patients with life-threatening or severely disabling autoimmune diseases possible. However, serious concerns remain regarding the toxicity and mortality of allogeneic HCT, caused primarily as a consequence of acute and chronic GVHD. Rare cases have been described in which autoimmune disease recurred after allogeneic matched sibling transplantation [8, 9, 13], but more experience is required to identify predisposing risk factors and the mechanism(s) of recurrence.

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Disease candidates and patient populations 

In general, patients selected to receive allogeneic HCT for autoimmune disease should have a high risk of mortality or severe disability that is unlikely to be cured by standard therapies, according to well-defined factors for a poor prognosis. Patients with systemic sclerosis, some patients with rapidly progressive and severe MS, high-risk systemic lupus erythematosus, pediatric lupus, severe therapy-refractory rheumatoid arthritis, severe autoimmune hematologic cytopenias, primary Sjögren syndrome with a systemic presentation, severe therapy-refractory vasculitis, pediatric Still disease, and dermatomyositis-polymyositis were discussed as potential candidates for allogeneic HCT. Some disease specialists expressed concern that detrimental graft-versus-host reactions might be triggered at nontypical sites, such as areas of central nervous system inflammation in patients with MS, but this concern is hypothetical at this time. A study intervention such as allogeneic HCT should occur before irreversible severe organ damage occurs. Certain patient subsets meeting disease-specific entry criteria, but with borderline organ function that would exclude them from autologous HCT clinical trials, may be candidates for studies of lower-intensity nonmyeloablative regimens and allogeneic HCT. Patients who experience treatment failure with autologous HCT for autoimmune disease and have an aggressive relapse might be candidates for clinical trials evaluating allogeneic HCT after nonmyeloablative conditioning regimens. Patients with rheumatoid arthritis have an excellent record of efficacy and safety after autologous HCT but also have an excessively high rate of posttransplantation disease relapse [14]. Although those with severe therapy-resistant rheumatoid arthritis may be candidates, it is difficult to recommend allogeneic HCT as a therapeutic option for most of these patients because several effective alternative therapies are available (Table 1).

Table 1. Allogeneic Hematopoietic Cell Transplantation (HCT) for Autoimmune Disease: Selected Disease Candidates and Potential Patient Populations Discussed at the Workshop

CNS indicates central nervous system.

The upper age limit for allogeneic HCT for autoimmune disease is recommended to be 50 to 55 years, which would encompass the ages for diagnosis of most autoimmune diseases; however, some participants suggested that a lower age limit of 45 to 50 years should be used. The risk of GVHD and other toxicities of HCT increases with increasing age. In addition, a functional thymus, which exists in younger patients, may be important for immune reconstitution and ensuing tolerance [15, 16, 17, 18], especially in the setting of mixed chimerism.

Identification of clinical, biologic, or genetic markers that are relevant to autoimmune disease processes or progression, that are specific for disease subtypes, or that are predictive of therapeutic responses would be an asset for clinical studies and the development of treatment plans. Unfortunately, there is a marked absence of such biomarkers for autoimmune diseases [19, 20, 21]. Inclusion of clinical and/or laboratory assessments based on the proposed mechanism of action of the therapy being investigated, for example, allogeneic HCT, would be one way to obtain further information about biomarkers for autoimmune diseases. The participants agreed that this should be an area of future investigation.

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Transplantation regimens 

In general, reduced-intensity and nonmyeloablative conditioning regimens produce less acute toxicity while still enabling donor engraftment, compared with standard myeloablative regimens, and are therefore preferred for clinical trials of allogeneic HCT for autoimmune diseases [22]. Different reduced-intensity and nonmyeloablative conditioning regimens vary in their degree of myelosuppression and immunosuppression. As a consequence, transplant-related toxicities can be variable, thus making it difficult to determine whether there is one preferred transplantation regimen. The treatment-related mortality (TRM) and the incidence of graft rejection and severe GVHD should be known for the regimens selected. In addition, these regimens should have accrued substantial experience obtained in more than one center to provide confidence in translation to multiple centers. There are several nonmyeloablative regimens for which experience is sufficient to merit consideration for patients with autoimmune diseases [23, 24, 25, 26, 27, 28, 29, 30]. However, because most experience with allogeneic HCT after nonmyeloablative conditioning is for patients who are too debilitated to receive conventional high-dose conditioning as a result of age and comorbid conditions, it is difficult to extrapolate transplant-related mortality risks for this group to the typically younger population of patients considered for HCT for treatment of autoimmune disease. These risks may vary depending on the underlying disease, organ function, and number and type of prior therapies. As more experience with nonmyeloablative regimens is obtained, it may be possible to select or adapt a preparative regimen depending on the particular disease indication and/or any preexisting organ dysfunction. With current nonmyeloablative regimens, the estimated risk of TRM for selected patients who are younger and have fewer comorbidities and prior therapies is as high as 10% to 15% and may be higher for older patients or those with medical comorbidities. Although the risk of TRM may prove to be less for several novel regimens currently in development, these cannot as yet be recommended for patients with autoimmune disease because there is little confirmatory experience in standard indications for HCT.

Similarly, strategies for GVHD prophylaxis vary, and no one approach is clearly superior to another. GVHD prophylaxis is generally considered within the context of the particular nonmyeloablative regimen, as an integral part of the regimen. Options for prophylaxis of GVHD include combinations of pharmacologic agents, T-cell depletion during preparation of the graft, or therapeutic in vivo and in vitro T cell–depleting antibodies. The risk of acute or chronic GVHD requiring systemic therapy is estimated to be 20% to 50% in the matched related donor setting and is related to several factors, including the conditioning regimen, the choice of GVHD prophylaxis, and the rapidity with which full donor T-cell chimerism is achieved. More aggressive strategies for GVHD prophylaxis typically result in a higher level of overall immunosuppression and a net increase in the risk of opportunistic infections and relapses. Therefore, development of more selective strategies for prophylaxis of GVHD that eliminate high levels of broad indiscriminate immunosuppression or overlapping toxicities of immunosuppressive drugs would be an important research goal.

Although the risk of TRM after allogeneic HCT will likely be higher than that after conventional therapy, the initial patients selected for these clinical trials will be those with a poor long-term prognosis, many of whom have disease that is resistant or refractory to standard treatments. Most patients meeting entry criteria will have failing internal organ function, poor quality of life, and significant disease-related morbidity and mortality, even though this may be delayed [31, 32, 33, 34]. On the basis of preclinical data and case reports, allogeneic HCT is expected to be highly effective for inducing sustained remissions or “cure” of autoimmune diseases. Furthermore, 80% of adult patients who survive 6 to 18 years after HLA-identical sibling transplantation have rated their quality of life as good to excellent and only 5% have rated it as poor, even though chronic GVHD requiring 1 to 2 years of immunosuppressive therapy developed after 33% of such transplantations [35]. For patients with aplastic anemia, the risk of death by the sixth year after allogeneic HCT is the same as that of an age- and sex-matched normal population [36]. Because of the potential for “cure” of disease, some patients may prefer allogeneic transplantation over standard care, even with the current rates of morbidity and mortality [37, 38]. Limitations caused by advanced autoimmune disease, as well as the economic implications of chronic disability, may be important to patients, even though they are difficult to quantify [39]. Therefore, in a risk-benefit analysis of treatments for autoimmune diseases, it may be appropriate to consider disease-related outcomes that include the severity of the disability, poor quality of life, and expected mortality, even though this may be delayed by 10 to 15 years.

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Stem cell source 

After nonmyeloablative conditioning, most transplantation strategies use hematopoietic stem cells collected from peripheral blood (peripheral blood progenitor cells; PBPCs). Grafts collected from peripheral blood after mobilization with growth factors contain substantial CD34⁺ and T-cell doses that minimize the risk of graft rejection [40]. Review of recent experience with unselected PBPCs as compared with bone marrow grafts for myeloablative allogeneic HCT is strongly suggestive, however, that a higher incidence or severity of chronic GVHD may be associated with PBPC grafts [41, 42, 43]. Therefore, bone marrow may be a preferred stem cell source for patients with autoimmune disease when a more intensive preparative regimen is used [23, 44]. Research of the optimal stem cell source and cellular content for hematopoietic cell grafts is therefore an area of active investigation [45]. Lack of successful prophylaxis strategies for chronic GVHD is a major barrier for more successful application of allogeneic HCT in nonmalignant disease.

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Donor source 

The hematopoietic stem cell donor source of choice for these initial studies of allogeneic HCT for autoimmune disease should be an HLA-identical sibling. The potential disadvantages of related donors are the genetic similarity, which might convey an increased susceptibility for the persistence or recurrence of the autoimmune disease after allogeneic HCT, and the limited availability of these donors. Therefore, the use of matched unrelated donors has certain theoretical advantages, and such donor sources should be considered in future trials after safety and efficacy are established in clinical trials with HLA-identical sibling donors. Current survival outcomes for traditional ablative allogeneic HCT using HLA 10/10 allele–matched unrelated donors in experienced centers are very similar to those after HCT from donors who are HLA-identical siblings [46, 47, 48]. The likelihood of finding a 10/10 allele–matched unrelated donor varies from 80% in certain Caucasian patient populations to as low as 20% in certain ethnic minorities [49, 50]. At this time, for safety reasons, umbilical cord blood or partially HLA-matched related donors are not recommended for clinical trials of allogeneic HCT in autoimmune disease.

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Graft manipulation 

CD34⁺-selected grafts have reduced T- and B-cell doses and are associated with a lower incidence and severity of GVHD after transplantation [51, 52]. In addition, manipulated grafts present an opportunity for future graft engineering research. Disadvantages of CD34⁺ selection include an increased risk of infection, a risk of graft rejection (especially after nonmyeloablative conditioning), and increased cell-processing costs and more complicated logistics. Experience with CD34⁺-selected grafts or with other graft manipulation for allogeneic HCT after nonmyeloablative conditioning is still limited, however, and in general should be pursued only after more experience has been obtained in patients with other diseases [53].

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Role of chimerism 

Current experience with allogeneic HCT for autoimmune disease is insufficient to establish the relation of mixed (partial donor) or complete (full donor) chimerism to clinical outcomes. The degree of chimerism necessary for disease control may vary for different autoimmune diseases. Theoretical advantages of mixed chimerism include less transplant-related morbidity (ie, GVHD), more rapid and comprehensive immune reconstitution after transplantation, and better immune tolerance. Theoretical disadvantages of mixed chimerism include an increased risk of graft rejection and a higher risk of recurrence of autoimmune disease [8, 9]. The relative importance of lineage specific chimerism—for example, T-cell subsets, B cells, natural killer cells, plasma cells, dendritic cells, or myeloid lineages—is not yet known [54]. It may be important to assess chimerism in situ (eg, in lymph nodes, thymus, and the central nervous system or other organs and tissues affected by disease) to develop a better understanding of the effect of mixed chimerism on the outcomes of autoimmune disease.

We recommend sequential monitoring of lineage-specific chimerism, at a minimum in myeloid, B-cell, and T-cell lineages, and, possibly, certain site-specific chimerism, in future allogeneic HCT protocols for autoimmune diseases. Highly quantitative methods, for example, analysis of short tandem repeats by polymerase chain reaction, are recommended [55, 56]. Long-term monitoring beyond 6 months should be considered to assess the persistence of mixed chimerism or the time to full donor chimerism, as well as the long-term stability of the graft. To appreciate therapeutic mechanisms in allogeneic HCT for autoimmune disease, it will be important to correlate the kinetics of establishment of donor chimerism with clinical events and other study end points.

For each nonmyeloablative allogeneic HCT regimen selected for clinical trials in autoimmune diseases, it will be advantageous to have baseline data available for the kinetics and extent of donor chimerism over time after HCT. This would be an important reference for clinical management should a patient experience recurrent autoimmune disease while a mixed chimera. For example, if a patient experiences early recurrence of autoimmune disease while donor chimerism levels are still increasing, does this represent a failure of treatment, or will the disease remit as full donor chimerism is achieved? We anticipate that such questions will also present a challenge for the design of clinical trials of allogeneic HCT for autoimmune diseases.

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Donor lymphocyte infusions 

Donor lymphocyte infusions (DLIs), provided either at predetermined intervals after allogeneic HCT as part of the transplantation protocol or as immune therapy after allogeneic HCT in the event of disease relapse, may be associated with inherent and not always predictable life-threatening risks—most importantly, GVHD and marrow aplasia. Because treatment failure after nonmyeloablative conditioning and allogeneic HCT may not necessarily have the same consequences for patients with autoimmune diseases as it would for patients with malignant diseases, use of DLI for patients with mixed chimerism and relapse of disease must be considered carefully. Use of DLI to control progressive autoimmune disease is unexplored and may offer an opportunity for therapeutic benefit in selected cases in which the risk of poor outcome after disease progression exceeds the risk of DLI administration [57]. It may be important to determine any changes in lineage-specific chimerism after DLI, and their relation to clinical events, in the setting of clinical research protocols. Use of modified DLI consisting of cell subsets or cultured cells with immunomodulatory properties, for example, may be an additional research opportunity when such cellular products are better understood and available for clinical use.

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Issues in clinical trial designs 

Research protocols consisting of carefully planned small pilot studies of allogeneic HCT as a therapeutic strategy for severe autoimmune diseases, performed by dedicated teams of transplantation and disease specialists, are recommended. Protocols should be well developed and focused on a single disease or subgroup of a disease, and the patient population should be clearly defined. The goal of such research studies should be to explore the safety, efficacy, and biology of allogeneic HCT for these diseases. Additional considerations and recommendations for the design of clinical trials of allogeneic HCT for autoimmune diseases are as follows:

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Other open research questions 

Additional considerations in allogeneic HCT for autoimmune disease are as follows:

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Conclusion/Next steps 

A rationale clearly exists for exploring the therapeutic and curative potential of allogeneic HCT for severe autoimmune disease. Although safer allogeneic transplantation strategies have become available, experience is currently insufficient to allow reliable extrapolation of data on safety and risks from patients with malignancies to patients with autoimmune diseases. At present, because of the limited experience and variable toxicity and outcome profiles associated with different conditioning approaches, it is not possible to definitively recommend one nonmyeloablative transplantation regimen over another. It is recommended that planning be initiated for clinical trials to generate safety and efficacy data for allogeneic HCT in patients with severe autoimmune diseases. Further development of novel allogeneic HCT regimens with even better safety and toxicity profiles is encouraged. Disease and transplantation expert task forces should be formed to define patient candidates within each disease type and the most appropriate transplant regimens. If the initial experience demonstrates adequate safety and potential efficacy, multicenter controlled trials will need to be conducted.

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Acknowledgments 

This workshop was supported in part by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, NIH, and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, MD, USA.

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Appendix 1. Workshop participants 

Cochairs 

Linda M. Griffith, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD); Richard A. Nash, Clinical Research Division, Fred Hutchinson Cancer Research Institute, University of Washington (Seattle, WA); Steven Z. Pavletic, Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (Bethesda, MD).

Speakers and Discussants 

Joseph H. Antin, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School (Boston, MA); Michael R. Bishop, Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (Bethesda, MD); Christopher N. Bredeson, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin (Milwaukee, WI); Richard W. Childs, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health (Bethesda, MD); Stephen J. Forman, Division of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center (Duarte, CA); Sergio Giralt, Department of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, University of Texas (Houston, TX); Alois Gratwohl, Departments of Hematology and Internal Medicine, University of Basel, Kantonsspital (Basel, Switzerland); Ronald Gress, Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health (Bethesda, MD); Chitra Hosing, Department of Blood and Marrow Transplantation, M.D. Anderson Cancer Center, University of Texas (Houston, Texas); Peter A. McSweeney, Blood and Marrow Transplant Program, Presbyterian/St. Luke’s Medical Center, Rocky Mountain Cancer Center (Denver, CO); Effie W. Petersdorf, Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington (Seattle, WA); Riccardo Saccardi, Bone Marrow Transplant Unit, UO Ematologia, Policlinico Careggi (Florence, Italy); Brenda M. Sandmaier, Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington (Seattle, WA); Judith A. Shizuru, Bone Marrow Transplantation, Stanford University Medical Center (Stanford, CA); Keith Sullivan, Division of Cellular Therapy, Department of Internal Medicine, Duke University Medical Center (Durham, NC); and John F. Tisdale, Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (Bethesda, MD).

James D. Bowen, Department of Neurology, University of Washington (Seattle, WA); Jacqueline Chen, Magnetic Resonance Spectroscopy Unit, Montreal Neurological Institute and Hospital, McGill University (Montreal, Canada); Hans Lassmann, Division of Neuroimmunology, Brain Research Institute, Vienna University Medical School (Vienna, Austria); Roland Martin, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (Bethesda, MD); Paolo A. Muraro, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (Bethesda, MD); Sridar Narayanan, Magnetic Resonance Spectroscopy Unit, Montreal Neurological Institute and Hospital, McGill University (Montreal, Canada); and Harry Openshaw, Department of Neurology, City of Hope National Medical Center (Duarte, CA).

Chiara Bocelli-Tyndall, EBMT Autoimmune Disease Working Party, Department of Rheumatology, Felix-Platter Spital (Basel, Switzerland); Philip J. Clements, Division of Rheumatology, Department of Medicine, University of California, Los Angeles School of Medicine (Los Angeles, CA); Daniel E. Furst (participation by teleconference), Division of Rheumatology, Department of Medicine, University of California, Los Angeles School of Medicine (Los Angeles, CA); Gabor G. Illei, National Institute of Dental and Craniofacial Research, National Institutes of Health (Bethesda, MD); Jacob M. van Laar, Department of Rheumatology, Leiden University Medical Center (Leiden, The Netherlands); Maureen D. Mayes, Division of Rheumatology, Department of Medicine, University of Texas-Houston Health Science Center (Houston, TX); James D. McNamara, Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda, MD); Barbara B. Mittleman, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (Bethesda, MD); John O’Shea, Lymphocyte Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (Bethesda, MD); Alan Tyndall, Department of Rheumatology, Felix-Platter Spital (Basel, Switzerland); and Michael M. Ward, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (Bethesda, MD).

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